Target Health Presenting at the Society for Clinical Trials


Target Health is pleased to announce that the Society for Clinical Trials (SCT) Program Committee has accepted the abstract “Quantum Leap – Leveraging Real-time (Direct) Data-Entry to Increase Speed, Improve Quality, and Dramatically Reduce Costs” for oral presentation in a Contributed Paper Session at the 34th Annual Meeting of the Society for Clinical Trials. The meeting will take place May 19-22, 2013 at the Sheraton Boston Hotel in Boston, Massachusetts, USA.


Dean Gittleman, Sr. Director of Operations, will present during the Session on Current Monitoring Practices on Wednesday, May 22 from 8:00 AM – 9:30 AM.


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

What is Tuberculosis?


Under a high magnification of 15549x, this colorized scanning electron micrograph (SEM) depicted some of the ultrastructural details seen in the cell wall configuration of a number of Gram-positive Mycobacterium tuberculosis bacteria. As an obligate aerobic organism M. tuberculosis can only survive in an environment containing oxygen.



Tuberculosis (TB) is a dreaded bacterial infection, known to humans since Neolithic times. It was commonly called 1) “___” at the turn of the last century because of the way the disease seemed to “consume” the individual it affected.


The bacteria causing tuberculosis is called Mycobacterium tuberculosis. It is spread through 2) ___ tiny droplets from the coughs or sneezes of an infected person. Spread of tuberculosis is facilitated by several factors like overcrowding, living in close quarters like in orphanages, prisons etc. and presence of other medical problems. Other medical problems that raise the risk of getting tuberculosis include malnutrition, alcoholism, presence of other infections like HIV infection that suppresses the 3) ___ system, etc. Babies and the elderly are at a greater risk due to their ill-developed and declining immune system respectively.


Getting the active disease means that the immune system fails to kill or contain the infection allowing it to spread to the 4) ___ or other parts of the body. This is called active tuberculosis. In some individuals the immune system cannot kill the bacteria, but manages to prevent it from spreading in the body. This can mean persistence of the bacteria in the body without producing 5) ___. This is called latent tuberculosis.


Tuberculosis mainly affects the lungs and is called 6) ___ tuberculosis. It can affect any part of the body including bones, brain, womb or the uterus, skin, lymph nodes etc. or may spread widely to other organs as seen in miliary tuberculosis and disseminated tuberculosis.


Typical symptoms of pulmonary tuberculosis include:


1.         continued or persistent cough of more than three weeks that brings up phlegm

2.         presence of streaks or drops of blood in the coughed up phlegm or sputum

3.         weight loss and fatigue and loss of appetite

4.         fever for a long duration that is not explained by any other cause

5.         night 7) ___


Tuberculosis is diagnosed using several laboratory techniques that test samples of 8) ___ and sputum. The bacteria can be found on staining and microscopic examination of the sputum. More rapid and sophisticated blood tests are also available to test for tuberculosis. A chest X ray is used to visualize the tubercular lesions in the lungs. CT scan and MRI images may also be used for 9) ___. For tuberculosis affecting lymph nodes, skin etc, the local lesion may be biopsied to detect tuberculosis bacteria.


With treatment, a TB infection can usually be cured. Treatment involves a course of antibiotics, usually for six months. More than one antibiotic is used to prevent emergence of resistance of the bacteria to the antibiotics. Those infected with a drug resistant form of tuberculosis may be prescribed a longer course of antibiotics. The Bacillus Calmette-Guérin (BCG) vaccine can provide effective protection against tuberculosis in most individuals. It is recommended in persons who are at a greater risk of the infection. Infants living in countries endemic for tuberculosis are routinely 10) ___ with BCG.


TB was a major health problem in most developed countries before the development of antibiotics. The number of cases has declined sharply after routine detection and use of 11) ___. However, in the last two decades cases of tuberculosis have gradually increased, especially among ethnic minority communities and immigrant population. In 2011, 8,963 cases of tuberculosis were reported in the UK (around 12 cases per 100,000 population). Of these nearly 6,000 cases were among population who were born outside the UK. There are many areas in the UK with much higher incidence rates, and those areas with incidence greater than 40/100,000. Pulmonary TB accounts for 60% of TB in the UK.


Tuberculosis is endemic in many developing and under-developed countries. Africa, particularly sub-Saharan Africa still suffers from a tuberculosis epidemic because of the increased susceptibility of the population due to concomitant 12) ___ infection. Source: Ananya Mandal, MD


ANSWERS: 1) “consumption”; 2) inhaling; 3) immune; 4) lungs; 5) symptoms; 6) pulmonary; 7) sweats; 8) blood; 9) diagnosis; 10) vaccinated; 11) antibiotics; 12) HIV



Egyptian mummy in the British Museum- tubercular decay has been found in the spines of Egyptian mummies.


Both strains of the tuberculosis bacteria share a common ancestor, which could have infected humans as early as the Neolithic Revolution. Skeletal remains show prehistoric humans (4000 BC) had TB, and tubercular decay has been found in the spines of Egyptian mummies dating from 3000–2400 BCE. Phthisis is a Greek word for consumption, an old term for pulmonary tuberculosis; around 460 BCE, Hippocrates identified phthisis as the most widespread disease of the times. It was said to involve fever and the coughing up of blood, which was almost always fatal. Genetic studies suggest TB was present in the Americas from about the year 100 CE.


Before the Industrial Revolution, folklore often associated tuberculosis with vampires. When one member of a family died from it, the other infected members would lose their health slowly. People believed this was caused by the original person with TB draining the life from the other family members.


Although the pulmonary form associated with tubercles was established as a pathology by Dr Richard Morton in 1689, due to the variety of its symptoms, TB was not identified as a single disease until the 1820s, and was not named tuberculosis until 1839 by J. L. Schoenlein. There is general agreement that consumption, the common name for tuberculosis in its early days, increased dramatically in Europe and North America during the seventeenth and eighteenth centuries and then began to decline. Death rates from tuberculosis peaked in the year 1800, a phenomenon linked to the socioeconomic became widespread somewhat later in the United States, because the movement of the population to large cities made overcrowded housing so common.


During the last 100 years in the thousands of years-long history of tuberculosis, there has been unquestioned scientific and clinical progress; but at the same time there has been a global increase in the number of victims and a worsening of the efficacy of control manifested by a rising prevalence of drug resistance in many countries. Today, tuberculosis is relatively easy to diagnose; when the right combination of medications is made available and taken by the patient, the disease can be cured more than 95% of the time; and in certain targeted populations, the manifestations of the disease can be attenuated by vaccination and even prevented by chemotherapy. Despite these remarkable achievements, the estimated number of new cases of tuberculosis in the world during each of the last several years has steadily increased: from 8.0 million in 1997 to 8.3 million in 2000, and is expected to reach 10.2 million in 2005. There are more people infected with Mycobacterium tuberculosis in the world this year than ever before, and from 1997 through 2000 the number of new cases of tuberculosis and the per capita incidence worldwide rose 1.8% per year and 0.4% per year, respectively.


Consumption was probably the most common killer of American colonial adults, and accounted for more than 25% of deaths in New York City between 1810 and 1815. Then a major reversal occurred and death rates began to fall. Three explanations have been advanced: improved socioeconomic conditions that led, in turn, to better nutrition and living and working standards; application of primitive public health measures; and the dawning realization that tuberculosis was probably an infectious disease and the beginning sequestration of (contagious) consumptives in hospitals and sanatoriums.


Toward the end of the nineteenth century, long after death rates from tuberculosis had begun their remarkable downward trend, two historic events occurred that had tremendous subsequent impact on the diagnosis and management of the disease. In 1882, Robert Koch discovered M. tuberculosis and in 1895, Wilhelm Konrad Roentgen discovered X-rays. These scientific triumphs were quickly applied to clinical medicine, so that around 1905, doctors could make a precise diagnosis of consumption by demonstrating abnormalities in a patient’s chest radiograph and finding tubercle bacilli in his or her sputum.


Even though mortality from tuberculosis in Western Europe and North America had declined substantially from its peak around 1800, 100 years later it was still huge: 194/100,000 in the United States, making it the third most common cause of death after cardiovascular diseases and influenza-pneumonia. At the turn of the twentieth century, there were only a handful of professional and governmental organizations specifically engaged with tuberculosis. On June 6, 1904, the efforts of both lay and professional concerned people, culminated in the formation of the National Association for the Study and Prevention of Tuberculosis (later the National Tuberculosis Association, the forerunner of today’s American Lung Association). The following year, members of the National Association who were also active in the burgeoning sanatorium movement founded the American Sanatorium Association (the predecessor of the American Trudeau Society, which was renamed the American Thoracic Society in 1960). Their first meeting was held in New York City on December 1, 1905; all 17 persons who attended and 17 others who were not present were elected to membership.


At the time the American Sanatorium Association was founded, there were only 106 sanatoriums in the United States, which provided 9,107 beds for patients with tuberculosis. By contrast, during its peak year, 1954, there were 108,457 beds allocated to the disease; the magical appearance of isoniazid 2 years earlier and the development of effective treatment for tuberculosis (described subsequently) ended the need for long-term institutionalization (of interest is the fact that one of the sanatoriums to close its doors in 1954 was probably the most famous of all: the Adirondack Cottage Sanatorium, renamed 2 years after its founder’s death in 1915 as the Trudeau Sanatorium).




In the 1880s, Louis Pasteur invented the principle and devised the original means of deliberately attenuating the virulence of a living microbe to produce a successful vaccine, first against fowl cholera and later against rabies and anthrax. Beginning in 1908, Albert Calmette and Camille Guerin borrowed Pasteur’s technique to create a vaccine against tuberculosis. After serendipitously learning that growth in ox bile diminished the virulence of Mycobacterium bovis, Calmette and Guerin meticulously performed 230 serial passages of a single isolate of the organism, sufficient for it to lose its ability to cause progressive fatal tuberculosis in a variety of animals: guinea pigs, rabbits, cows, horses, monkeys, and chimpanzees. The attenuated bacilli did, however, induce self-limited infection as well as its accompanying state of partial resistance to reinfection with virulent M. tuberculosis and M. bovis. Not surprisingly, the bacteriologists called their vaccine Bacille Bilie (from bile) Calmette et Guerin, which was quickly shortened to Bacille Calmette Guerin, and then to its household name, BCG.


Various pharmaceutical tuberculosis treatments and their actions


Tuberculosis bacteria


With extreme prudence and caution, beginning in 1921, BCG was administered to an increasing number of babies and young children; by 1924, more than six hundred infants had been vaccinated with apparent protection and few serious side effects. BCG started to attract attention and to be more widely used until late 1929 and early 1930 – when a dreadful catastrophe intervened. According to Daniel, 251 babies in Lubeck, Germany were mistakenly given living virulent M. tuberculosis instead of impotent BCG. Tragically, 72 infants died, all but five from acute tuberculosis (the number of vaccinees and deaths in the incident vary slightly from one account to another, but the essential facts are indisputable). Not enough attention, though, has been paid to the other 179 victims, the majority of whom developed clinical tuberculosis and a few others who remained healthy but developed positive tuberculin tests. Twelve years later, every one of these children was alive and free of tuberculosis, an evident demonstration that even in immunoincompetent infants, heavy inoculation with tubercle bacilli is by no means invariably fatal.


Despite this setback, BCG has been given to untold millions of people and, not long ago, was the world’s most commonly used vaccine. Efficacy rates have varied enormously, from 0 to 80%. Immunization seems most helpful in infants, protecting them from severe forms of tuberculosis, particularly miliary and meningeal disease, a conclusion that fits with the old observation that BCG-induced immunity does not prevent the subsequent establishment of infection with tubercle bacilli, but only retards their spread.


M. tuberculosis is a tough and resilient microorganism that is well adapted to prolonged residence in its human host. Shielded by a waxen cell wall that protects against lethal enzymes and other deadly products elaborated by the body’s antibacterial defenses, tubercle bacilli are also sheltered against foreign chemicals such as gold, arsenic, mercury, calcium, iodine, quinine, creosote, turpentine, cod liver oil, and chaulmoogra oil, to mention just some of the many “therapeutic” substances of historical interest that had been tried in a fruitless effort to arrest or reverse the progress of consumption.


The first hint of a chink in the waxy armor of M. tuberculosis was discovered by physician and zoologist H. Corwin Hinshaw and his veterinarian colleague William Feldman during tests of Promin in their experimental model of tuberculosis in guinea pigs. In 1941, they reported, “The results of this investigation seem to indicate that experimental infection with tubercle bacilli, as in the case of infections with certain other pathogenic bacteria, may be retarded or actually be subdued by a chemotherapeutic agent.” Subsequent clinical studies on Promin and a promising derivative, Promizole, in patients with tuberculosis came to a halt, however, because of the discovery by Selman Waksman, a distinguished soil microbiologist, of a new and even more promising antibiotic: streptomycin.


In January 1944, Schatz, Bugie, and Waksman reported their discovery of streptomycin and detailed its potency against 22 different species of bacteria, including M. tuberculosis. In their table of results, they presented indisputable evidence that streptomycin was active against tubercle bacilli, but nowhere else in the article is that seminal fact mentioned or discussed. In looking back on this oversight, Birath observed, “No comment whatever on this sensational find is to be found in the text. The attention was wholly directed on other findings. The discovery had consequently been made, but was not discovered by the discoverers themselves!” Several months later, Schatz and Waksman did go back and retest streptomycin against M. tuberculosis, largely because the strain they used in their first experiments was harmless and they wanted to be sure the antibiotic could kill virulent (H37) tubercle bacilli.


Hinshaw and Feldman knew about Waksman’s work practically from its beginning and had tried to obtain some streptomycin for testing in their guinea pigs as early as November 1943, exactly 4 weeks after Schatz isolated the two strains of Actinomyces that produced the antibiotic; 10 grams of the precious material finally arrived at the Mayo Clinic in April, 1944, enough to treat only four guinea pigs. No doubt, though, about the outcome after additional experiments: “a marked and striking difference in the results of the tuberculous infection between the controls and the treated animals.” Next, on November 20, 1944, only 15 months after the discovery of streptomycin, in collaboration with Karl Pfuetze, and while further guinea pig experiments were still underway, Hinshaw and Feldman began treatment of the first human subject to receive long-term streptomycin: Patricia, a young woman who was clearly dying from progressive pulmonary tuberculosis. Patricia miraculously survived but had a prolonged recovery; she left the hospital, got married, had three children, and led an active life. Others lucky enough to be treated also did well.


Streptomycin was good, but far from perfect. It had significant eighth nerve toxicity and its benefits were often short lived owing to the development of resistance by the bacteria. Fortuitously, the future of chemotherapy of tuberculosis was saved by the nearly simultaneous development of another active agent, para-aminosalicylic acid (PAS), by Jorgen Lehmann in Sweden. Lehmann’s discovery resulted from pure deduction based on published information that M. tuberculosis avidly metabolized salicylic acid. Lehmann wanted to find a look-alike substance that hungry bacilli would feast on but that would kill rather than nourish. That chemical turned out to be PAS. After a series of promising laboratory studies, in partnership with Gylfe Vallentin, a distinguished tuberculosis specialist, Lehman tried PAS in patients – initially by direct instillation into tuberculous empyema pockets; then, on October 30, 1944, orally. The first patient to receive systemic PAS was a moribund young woman named Sigrid who made a dramatic recovery; other patients also improved. But clinical acceptance of the drug in Sweden was slow, much slower than that of streptomycin in the United States. As a consequence, even though Sigrid was treated with PAS 1 month before Patricia received streptomycin, in the chronicle of medical history, PAS appeared 2 years after streptomycin.


Like streptomycin, PAS often produced only transient clinical benefit before mycobacterial resistance developed. Shortly thereafter, the British Medical Research Council showed how this could be diminished. On the basis of preliminary evidence from the United States, a landmark clinical trial definitively documented the superior value of combined treatment with streptomycin and PAS compared with either agent alone. Not only did the trial establish one of the axioms of the therapy of tuberculosis – never use a single agent to treat active disease – it introduced the statistical technique of random allocation of subjects to one treatment arm or another, a vital means of maximizing the experimental value of the scant supply of streptomycin. When administered together, streptomycin preserved the potency of PAS by preventing tubercle bacilli from becoming resistant to it, and vice versa. Plus, two antituberculosis agents have more therapeutic clout than just one.


In 1951, in what must be one of the most extraordinary pharmaceutical coincidences of all time, it turned out that scientists at Bayer Chemical in Germany and at both Squibb and Hoffmann-La Roche in the United States had discovered exactly the same miracle agent at exactly the same time – isoniazid, the wonder drug that everyone had dreamed of: powerful, safe, and inexpensive. It didn’t take long to learn that most patients with pulmonary tuberculosis could be cured with combined therapy with isoniazid, streptomycin, and PAS; streptomycin had to be stopped after a few months, but it was necessary to take the other two antibiotics for a total course of 18 to 24 months. “Triple therapy” remained the standard treatment for all forms of tuberculosis for nearly 15 years. Not only did sanatoriums close, but also therapeutic mainstays like pneumothorax and pneumoperitoneum became obsolete, and surgical procedures such as thoracoplasty and the surgeons who did them disappeared. Finally, the availability of rifampin in the mid-1960s and the rejuvenation of pyrazinamide, an older agent that had been shelved owing to its toxicity, allowed the development of modern “short-course” antituberculosis chemotherapy, a particular triumph of Wallace Fox and Dennis Mitchison, and testimony to the wisdom of the long-term support of tuberculosis research provided by the British Medical Research Council. It was finally accepted that treatment of tuberculosis – from beginning to end – could be given entirely on an outpatient basis, without hospitalization, something Fox proclaimed in 1959, from studies in his (later) celebrated Tuberculosis Chemotherapy Centre in Madras, India.




Beginning in 1953, the year the current system of accurate national data collection and notification was installed, there was a steady annual decline of around 5-7% in the per capita incidence rate of reported cases of tuberculosis in the United States. In 1985, the rate went down again, but only slightly. In 1986, the unthinkable happened – for the first time in 33 years, the incidence rate of tuberculosis increased compared with the rate the previous year. The actual numbers of reported cases tell the story even better: in 1953, 84,304 Americans developed tuberculosis and 19,707 died of it; in 1985, the nadir of the three-decade-long reduction, there were 22,201 new cases and only 1,752 deaths. Thereafter, both the numbers of newly reported cases and the incidence rates edged upward, finally peaking in 1992, before resuming another steady decrease.


The reasons for the resurgence are complex, but four factors have generally been implicated: the arrival and spread of HIV infection; immigration of people from high-prevalence countries; the development of “hot spots” (e.g., hospitals, shelters, prisons) where tuberculosis flourished; and the deterioration of tuberculosis control. New York City was particularly hard hit. In 1992, the apex of the resurgence, although a large city, New York’s inhabitants accounted for only 3% of the total U.S. population; in contrast, the same year, the city’s 3,811 registered cases of tuberculosis comprised 14% of all those in the country. To compound the problem the “Big Apple” hosted 61% of the nation’s entire burden of patients with multidrug-resistant tuberculosis.


In an exercise of poor judgment framed in the belief that the consistently declining rates of tuberculosis in the United States meant that the disease was no longer a threat – and over the dire predictions of public health experts – the U.S. Congress decided to save money by changing tactics. Between 1970 and 1972, “categorical” (i.e., earmarked) federal funds for tuberculosis control were phased out and lumped together with several other categorical programs in the form of “block grants,” which were awarded to states for communicable diseases as a whole. States would know how best to use the largess and they were no longer required to allocate any funds at all to tuberculosis. After that switch, there was no way of knowing exactly how much the states did spend and for what activities, but there is little doubt that, overall, funding for tuberculosis control was, as the Institute of Medicine lamented, “sharply curtailed.”


New York City’s Bureau of Tuberculosis Control was rendered helpless: staffing and services shrank to their all-time low and outpatient clinics were cut from 24 to 8. The fiscally induced programmatic dismantling occurred while the number of homeless was climbing; more and more people were turning to alcohol, heroin, and cocaine; mental institutions were shedding patients into the streets; and large numbers of immirants from high-prevalence countries arrived laden with M. tuberculosis. Then, the catalyst of HIV-AIDS kicked in and the case rates of tuberculosis throughout New York City – particularly in Harlem – which had been dropping, changed directions and soared


A high percentage of patients with tuberculosis who had been started on appropriate treatment while hospitalized were lost to follow-up after discharge: the inevitable consequence – multidrug-resistant tuberculosis. There are many countries and regions within countries throughout the world where promiscuous treatment and management practices have created rates of multidrug-resistant tuberculosis. Beginning in 1992, the Bureau of Tuberculosis Control greatly augmented its staff, upgraded its facilities, and set to work. Within 4 years, nearly 80% of all New Yorkers with tuberculosis were receiving directly observed treatment, which led to a decrease both in the number of reported cases and in the prevalence of multidrug-resistant strains of tubercle bacilli. The cost of congressional oversight was over $1.0 billion.




In the mid-1970s, Czech, Karel Styblo MD, (known as the “father of modern TB epidemiology” and the “father of modern TB control”) harnessed the meager resources of the International Union against Tuberculosis and Lung Disease and showed that, contrary to expert opinion, tuberculosis could be controlled in extremely poor countries: beginning in Tanzania, one of the poorest of them all. Comparable successes attended the establishment of similar programs in many other impoverished countries. Styblo’s approach – high-level political commitment, detection of cases by direct sputum-smear microscopy, provision of a regular and reliable supply of antibiotics and reagents, direct observation of medications being swallowed, and accurate recording and reporting of results – was later adopted, packaged, and promoted by the World Health Organization (WHO) under the rubric, Directly Observed Therapy Short-Course, better known as “DOTS.” The DOTS strategy has proved to be an efficient, although underused, methodology for national programs to deal with tuberculosis. But neither Styblo nor the WHO could possibly have foreseen the coming of HIV–AIDS and, with it, the undoing of tuberculosis control efforts in virtually all countries throughout the world where the two infections coexist in large numbers.


HIV infection is now recognized as the most powerful risk factor ever identified, that enhances the progression of tuberculous infection, whether recently or remotely acquired, to clinically active tuberculosis. Accordingly, tuberculosis is one of the leading worldwide causes of morbidity and mortality among people with HIV-AIDS. In the year 2000, of the estimated 8.3 million new cases of tuberculosis, 9% were attributable to coexisting HIV infection, but the proportion was much higher (31%) in Africa and the situation is worsening.


Most of the increased number of cases of tuberculosis projected during the year 2005 are HIV-linked and will occur in sub-Saharan Africa. There is no longer any doubt: spreading HIV infection is the main force driving the global resurgence of tuberculosis, and current efforts, including DOTS, to deal with rising case rates in heavily HIV-afflicted countries have failed. Judging from this historical perspective, as long as HIV continues to worsen in countries with a high background prevalence of tuberculous infection, as is forecast, the future of worldwide tuberculosis looks bleak – until at least one member of the “cursed duet” is brought to a halt with an effective vaccine.


In 2007, the prevalence of TB per 100,000 people was highest in sub-Saharan Africa, and was also relatively high in Asia.



The World Health Organization and the Bill and Melinda Gates Foundation are subsidizing a new fast-acting diagnostic test for use in low- and middle-income countries. Many resource-poor places as of 2011 still only have access to sputum microscopy.


The BCG vaccine has limitations, and research to develop new TB vaccines is ongoing. A number of potential candidates are currently in phase I and II clinical trials. Two main approaches are being used to attempt to improve the efficacy of available vaccines. One approach involves adding a subunit vaccine to BCG, while the other strategy is attempting to create new and better live vaccines. MVA85A, an example of a subunit vaccine, currently in trials in South Africa, is based on a genetically modified vaccinia virus. Vaccines are hoped to play a significant role in treatment of both latent and active disease.

To encourage further discovery, researchers and policymakers are promoting new economic models of vaccine development, including prizes, tax incentives, and advance market commitments. A number of groups, including the Stop TB Partnership, the South African Tuberculosis Vaccine Initiative, and the Aeras Global TB Vaccine Foundation, are involved with research. Among these, the Aeras Global TB Vaccine Foundation received a gift of more than $280 million (US) from the Bill and Melinda Gates Foundation to develop and license an improved vaccine against tuberculosis for use in high burden countries.


A number of medication are being studied for multi drug resistant tuberculosis including: bedaquiline and delamanid. Bedaquiline received U.S. Food and Drug Administration (FDA) approval in 2012. The safety of these new agent is still uncertain as the number of people in which they have been studied is small.


Tuberculosis, during the last 100 years, has highlighted two distinct and diverging movements: first, the great progress in scientific knowledge and its clinical application that has made consumption a diagnosable and curable disease; second, the rising numbers of cases and alarming rates of drug resistance worldwide. Together, these phenomena provide another example of the paradox: that advances in the treatment of individual patients do not easily translate into global public health gains. When we look back on tuberculosis 100 years from now, hopefully, we will find that the distorted political and economic forces that shape health care have been brought into balance and that this ancient scourge has finally been eradicated.


Benefits of Quitting Smoking Outpace Risk of Modest Weight Gain


According to an article published in the Journal of the American Medical Association (2013;309:1014-1021), post-cessation weight gain does not elevate cardiovascular risks for former smokers The improvement in cardiovascular health that results from quitting smoking far outweighed the limited risks to cardiovascular health from the modest amount of weight gained after quitting. The study also found that former smokers without diabetes had about half as much risk of developing cardiovascular disease as current smokers, and this risk level did not change when post-cessation weight gain was accounted for in the analysis. This study is the first epidemiological effort to directly address the health impact of the weight gain that many people experience following smoking cessation.


The study team analyzed data collected between 1984 and 2011 from 3,251 participants enrolled in the NHLBI’s Framingham Heart Study. During this time, participants received periodic medical exams so that changes in weight and smoking status could be calculated. Participants were divided whether they had diabetes or not, then further divided into four smoking categories: smokers, non-smokers, recent quitters (quit for four years or less), and long-term quitters (quit for more than four years). The researchers then examined the occurrence of cardiovascular problems such as coronary heart disease, stroke or heart failure in each group.


The initial analysis, which did not account for any changes in weight, found that former smokers without diabetes had about half as much risk of cardiovascular problems as smokers (0.47 times the risk for recent quitters and 0.46 for long-term quitters). By comparison, non-smokers had about one-third as much risk (0.32). The authors then made statistical adjustments to account for the fact that recent quitters gained more weight on average than other groups (about 6.5 pounds). Even accounting for weight, the lowered risk remained nearly the same for recent quitters (going from 0.47 to 0.49 times the risk). The lowered risk for long-term quitters and non-smokers remained constant when adjusting for weight gain.


According to the authors, the findings suggest that a modest weight gain, around 5-10 pounds, has a negligible effect on the net benefit of quitting smoking but being able to quantify to some degree the relationship between the benefits and side effects of smoking cessation can help in counseling those who have quit or are thinking about quitting. The authors added that the analysis could not definitively conclude the role of modest weight gain in former smokers with diabetes, though the numbers suggested a similar trend. It was noted that follow-up studies to confirm this negligible effect of weight gain in people with diabetes would be important, as weight control is a key factor in managing diabetes and preventing diabetes-related heart problems.

Regulatory Innovation and Drug Development for Early-Stage Alzheimer’s Disease



The following was abstracted from an article published in the New England Journal of Medicine 13 March 2013) and authored by Nicholas Kozauer, M.D. Medical Officer, and Russell Katz, M.D., Director, both of the Division of Neurology Products (DNP) at FDA.


In reviewing new-drug applications for the treatment of Alzheimer’s disease (AD), the FDA has maintained that claims of improved cognition should be accompanied by evidence of improvement in function. However, the premise that effective cognitive improvement will be manifested in the functional assessment of patients is untenable in the case of early-stage AD, which is increasingly the target of drug-development efforts. However, drug-development tools that are validated to provide measures of function in patients with Alzheimer’s disease before the onset of overt dementia are not yet available. Improvement in function, moreover, could lag substantially behind cognitive improvement mediated by pharmacologic agents early in the course of the disease. In view of the devastating effects of this disease on patients and their families, along with its growing prevalence, innovative approaches to trial design and end-point selection are urgently needed, especially as the drug-development community turns its sights on early stages of the disease.


The current landscape of research and drug development in AD offers a study in contrasts. On the positive side, numerous discoveries over the past decade have begun to unmask complex pathophysiological processes that underlie disease progression. Such advances have, in part, resulted from large, well-organized observational studies, such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI), that have elucidated various disease biomarkers that reflect, or even predict, the progression of disease. On the negative side, drug discovery has been disappointing. Despite all best efforts to translate mechanistic insights concerning AD into new drug products, several candidate agents have failed to demonstrate efficacy in large, well-designed, phase 3 clinical trials of late-stage disease.


The hallmark pathological feature of AD is the presence of brain plaques, consisting primarily of beta-amyloid peptide aggregates. Accordingly, the abnormal production and aggregation of beta-amyloid peptide, associated particularly with late-stage disease, has been the principal target of many drug-development efforts, including the recent phase 3 efforts that failed to result in new drug products. To account for these disappointing results of trials involving patients with overt dementia, a leading theory posits that the attempts at intervention may have been made too late in the progression of disease, at a stage when neuronal damage had become too widespread. According to some models, levels of beta-amyloid peptide in the brain reach a plateau before the earliest symptoms of AD are apparent. A further hurdle to interpreting clinical failures is our limited understanding of how beta-amyloid production may contribute to the pathophysiology of the disease. Because the biologic role of beta-amyloid peptides is uncertain, researchers are also investigating alternative targets of intervention at various stages of progression.


The focus of drug development in AD has increasingly been earlier disease stages, before overt dementia. This refinement of focus, however, raises important new challenges because the subtleties of cognitive impairment in patients with early-stage AD can be difficult to assess. Moreover, the range of focus must extend to healthy people who are merely at risk for the disease but could benefit from preventive therapies. In recognition of these shifting challenges, the FDA has developed guidance for the design and execution of clinical trials involving patients who do not present with dementia.


One aspect of the FDA guidance covers the selection of patients for trials in early-stage AD. In particular, FDA has acknowledged the consensus emerging within the AD research community that clinical diagnosis of early cognitive impairment might be paired productively with appropriate biomarkers of disease – criteria that have been delineated and are being validated by various working groups.3,4 Such biomarkers might include brain amyloid load (e.g., as measured by positron-emission tomography) and cerebrospinal fluid levels of beta-amyloid and tau proteins. Ongoing efforts by the research community to qualify biomarkers in clinical trial designs and methods for enriching study populations with patients with early-stage AD reflect important FDA priorities.


A specific suggestion that is also offered in the FDA’s guidance for trials focusing on patients in whom overt dementia seems imminent is the use of a single scale that combines assessment of both cognition and function, such as the score on the Clinical Dementia Rating Sum of Boxes (CDR-SB), which rates patients on a series of six domains covering various aspects of cognition and daily functioning. For patients whose disease is at an even earlier clinical stage, so that functional impairment would be more difficult to assess, it might be feasible to approve a drug through the FDA’s accelerated approval pathway on the basis of assessment of cognitive outcome alone. The accelerated-approval mechanism allows drugs that address an unmet medical need to be approved on the basis of a surrogate end point or an intermediate clinical end point (e.g., a sensitive cognitive measure), with the stipulation that postapproval studies will be conducted to verify the clinical benefit. Such a regulatory process may hold promise for facilitating the approval of treatments that appear to be effective in early AD, when patients might be expected to derive the greatest benefit.


Despite our growing understanding of the relationship between various disease-based biomarkers and the clinical course of AD, it remains unclear whether the effect of a drug on one or more such biomarkers can actually predict a meaningful clinical benefit. This concern was reinforced by the recent phase 3 trials of amyloid-lowering agents that failed to improve cognition despite appearing to interact with putative targets in the brain. It remains possible that an effect of an intervention on one or more biomarkers could someday be accepted as predictive of a clinical benefit, but further research will clearly be needed before the effect of an intervention on a single biomarker alone could be considered an adequate surrogate measure for the purposes of accelerated approval of a candidate drug for early AD.


As the focus of drug development has shifted to earlier stages of AD, many new and challenging scientific questions have emerged, and the regulatory framework under which such therapies are evaluated should evolve accordingly. The FDA remains committed to innovative approaches to the evaluation of drugs that are in clinical development. Effective treatments for the devastating disorder that is AD are urgently needed, as the world’s population continues to age.

Job Strain-Associated Inflammatory Burden and Long-Term Risk of Coronary Events


According to an article published online in Psychosomatic Medicine (4 March 2013), a study was performed to examine the association between job strain and coronary heart disease (CHD) and the role of markers of inflammation and endothelial dysfunction, as possible mediators of job strain-associated CHD risk.


The study population (n = 1027) included employed participants (35–64 years old, 68% male) from the population-based MONICA/KORA (Monitoring of Trends and Determinants in Cardiovascular Disease/Kooperative Gesundheitsforschung in der Region Augsburg) studies. At baseline Karasek’s Job Strain Index was assessed during standardized personal interviews, and nine biological markers were measured (1984-1995). Participants were followed (average, 12 years) to assess incident events (sudden cardiac death or fatal and nonfatal myocardial infarction). In this case-cohort design, the final sample contained 114 cases and 913 noncases.


Results showed that baseline distributions of cardiometabolic risk factors were significantly different between cases and noncases, with no detectable job strain-specific differences. However, cases with high job strain had higher monocyte chemoattractant protein-1, interleukin (IL)-8, and IL-18 compared with noncases with high job strain. High-sensitivity C-reactive protein, IL-6, and soluble intercellular adhesion molecule-1 were increased in cases versus noncases, regardless of work stress. Job strain was associated with incident coronary events in Cox proportional hazards models adjusted for age, gender, and survey (hazard ratio = 2.57) and after adjustment for CHD risk factors (2.35). Adjustment for monocyte chemoattractant protein-1 or IL-8 increased this risk estimate by 14.5% or 9.4%, respectively, whereas adjustment for C-reactive protein and soluble intercellular adhesion molecule-1 led to decreased hazard ratios (-9.9% and -5.5%, respectively).


According to the authors, job strain increased CHD risk in healthy workers and the associated inflammatory burden may contribute to stress-related coronary pathogenesis.

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Working with the FDA Office of the Ombudsman



Posted on March 13, 2013 by FDA Voice


Like many Federal agencies, FDA has a robust ombudsman program that addresses concerns and complaints from regulated industry and the public. At FDA, most product evaluation centers house their own ombudsman staff that address center specific issues. The FDA Office of the Ombudsman, as part of the Office of the Commissioner, provides this function for the agency as a whole.


While some think of an ombudsman as a type of court of last resort or legal adviser, the FDA Office of the Ombudsman rather acts primarily as a counselor or informal mediator. An ombudsman may be called upon by interested parties to provide guidance and assistance at any stage in a dispute, complaint, or other problem that relates to the work of the agency – not only when a matter reaches an impasse. Addressing problems early can often aid in their resolution.


The FDA Office of the Ombudsman employs some basic guiding principles that allow it to serve in this mediating role:


Neutrality – to engage in matters free from bias and independently from the agency components involved;


Transparency – to strive to be as clear and open as possible about the steps we are taking to provide assistance and about what we can and cannot do to help;


Confidentiality – to maintain the confidentiality of all information provided consistent with applicable laws and regulations.


The FDA Office of the Ombudsman handles inquiries about the resolution of consumer complaints as well as inquiries from regulated industry regarding, among other things, agency action or delays in action, compliance activities, import issues, and actions of FDA field offices. The Office plays an important role in assisting small businesses. Although small businesses are generally subject to the same regulations as any other entity, the Office can help to draw attention to the special needs and concerns of these companies. If nothing else, the Office can help small businesses to understand messages from the agency and to better communicate with FDA offices and staff, thereby helping companies to satisfy FDA requirements, which are designed to protect consumers and patients.


The tools used to assist individuals and companies vary from situation to situation. Sometimes the Office helps companies and individuals to better understand actions taken by FDA. At other times the Office can be helpful in calling attention to and moving forward action that has been delayed. In many instances, the Office is able to facilitate a productive meeting between key FDA officials and the interested party to discuss and help move toward resolution of issues of concern.


A new role for the FDA Office of the Ombudsman is in shepherding the consideration of scientific disputes raised by FDA employees that are not resolved elsewhere and rise to the level of the Commissioner. While there are often multiple legitimate ways to view different findings and to make regulatory or policy decisions, FDA is committed to the integrity of the underlying science and a science-based approach to its decision making, and places great value on ensuring that divergent scientific opinions are fully and fairly heard. Any FDA scientist can first raise a scientific dispute or disagreement within the center where they work through well-defined processes, with the final arbiter being the Director of that FDA center. However, if they are ultimately not satisfied that their views have been fully heard and considered by the Center, they can bring the matter to the Office of the Commissioner via the FDA Office of the Ombudsman for review of the process.


Whatever the issue, question, or problem, the FDA Office of the Ombudsman stands ready to provide guidance and assistance. They are here to help and if they can’t directly provide assistance in a given matter, they will identify the FDA component that can. The contact email is


Laurie Lenkel is Ombudsman and Andrew Moss is Deputy Ombudsman in FDA’s Office of the Commissioner.

Green Bean Arugula Salad with Avocados, Pears, Olives, Cheese


This salad is so-o scrumptious, everyone is gonna want more. There’s something special about the way the flavors of these ingredients mingle.


As a warm weather meal, it can’t be beat and it’s starting to get warmer here in New York. In March, you could start with a hot soup (in summer, serve a cold soup) and then this fabulous salad, with a selection of warm breads, a fruit and cheese platter and nice cool glasses of Sauvignon Blanc.   Life is good!




1.5 pounds green beans

2 cups arugula (wash at least two times)

2 medium-sized ripe avocados

1 firm Asian pear (or Bosc pear)

1/2 cup sliced pitted black olives

1/2 cup crumbled blue or gorgonzola cheese

6 Tablespoons olive oil

2/3 cup Cilantro, chopped

Juice of 1/3 lemon x 2

Pinch Salt

Pinch pepper

1 garlic clove, juiced (use 2 if you like garlic)




Steam the green beans, until slightly cooked, al dente – not mushy. Rinse under cold water to stop them from cooking (and enhance the beautiful green color) and dry with paper towel.


Wash arugula several times, until all sand is out – dry with paper towel


Mix the Olive oil with the fresh 1/3 lemon juice, garlic juice, pinch salt, pinch black pepper


On the same plate, (keep the skin on the pear), slice the pear lengthwise with a mandoline, then cut each slice in half. Slice the avocados. Now, drizzle the other 1/3 fresh lemon juice over the pear and avocado slices


In your salad bowl, add the green beans, arugula and olives. Toss gently. Then, add the pear and avocado slices and crumbled cheese. Finally, slowly pour the dressing over the salad. Use a spatula to get every drop of the dressing poured over the salad. Toss very gently, so as not to break the pear and avocado slices, and serve.


You are in for a treat with this delicious salad.