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The global reaction to Nasa’s arsenic bacteria research; plus, Dr Petra Boynton exposes some dating myths
Target e*CRF® Since 1999
Since 1999, Target Health Inc. has released approximately 250 EDC studies; and 54 studies are currently ongoing. In addition to the eCRFs, in this same time frame, we did about 30 paper based trials, mostly in the earlier years, though a few still trickle in. About half of our studies now use central randomization, where Target e*CRF assigns drug/device treatment.
All of our eCRF screens are built in English. Some eCRF studies used translated paper version of patient diaries (e.g. Spanish, German, Hebrew, etc.) but the data were entered in English.
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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. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog.
Deadly Gram-Negative Germs
Gram-negative 1) ___ are practically built to withstand drugs, which is one reason few drug makers have rushed to pursue treatments.
The bacteria have a double cell 2) ___ to shield them, compared with Gram-positive organisms, which have a single membrane. They can make various enzymes that break down 3) ___. And some, particularly Pseudomonas aeruginosa, have powerful pumps that can expel the drugs.
The bacteria also readily exchange genes, even across different species, that confer drug 4) ___. It is likely to be several years before new drugs to treat Gram-negative infections are available. A report last September by European health authorities found only six novel drugs in clinical trials that might work against at least one Gram-negative 5) ___, compared with 13 for Gram-positive bacteria.
A separate study released about a year ago by the Infectious Diseases Society of America found no drugs in middle- or late-stage clinical 6) ___ directed specifically at Gram-negative organisms. There were eight drugs in those trials that developers hoped might work against both Gram-negative and Gram-positive microbes.
The difficulty of killing Gram-negative germs is not the only reason for the dearth of new drugs. Another is that many big drug companies have scaled back or abandoned antibiotic development. Antibiotics are typically taken for only a week or two, after which the patient is cured. They are simply not as lucrative as drugs for other 7) ___ that are taken for a long time to manage a long-term condition.
The thin pipeline has raised the value of the few 8) ___ under development for Gram-negative infections. In the last three months, three small companies at work on such drugs – KaloBios Pharmaceuticals, Calixa Therapeutics and Novexel – have either licensed their drugs to bigger companies or have been acquired. Source: The NY Times, by Andrew Pollack
ANSWERS: 1) bacteria; 2) membrane; 3) antibiotics; 4) resistance; 5) organism; 6) trials; 7) diseases; 8) drugs
The Death of Marat (1743-1793)
Many people recognize the (above) famous masterpiece, called The Death of Marat, by painter, Jacques Louis David; however, most may not know that the subject was Swiss-born doctor, Jean-Paul Marat, who went from being the king’s physician to the most ruthless proponent of the guillotine. His assassin said she “had killed one man to save a hundred thousand” – an unusual claim to make against a doctor.
Jean-Paul Marat was born in 1743 into a lower middle class family in Geneva. His father was a well-educated Sardinian who had moved to Switzerland where he converted to Calvinism. There he was viewed as an outsider, and he found it difficult to obtain employment. The young Marat, influenced by his father’s experiences, left Geneva aged sixteen and travelled across Western Europe, and eventually settled in London, where he studied medicine and worked as a physician. His first publication was entitled “The philosophical essay of Man” and it outlined Marat’s beliefs that the soul was to be found in the meninges of the brain and that a true understanding of philosophy can only come after an understanding of physiology.
This clashed with the philosophy of the day and attracted the ire of Voltaire who wrote a scathing criticism of the work. Such a strong attack from such a prominent figure brought public attention to Marat’s work and for the remainder of his life Marat would remain a famous figure.
From London he moved to Newcastle where he practiced human and veterinary medicine. In 1774 he published his first political work entitled “Chains of Slavery”. It had revolutionary sympathies and included a call to end the monarchy. It was popularly believed that in order to complete the 65-chapter work, Marat ate nothing, drank only coffee and slept for just two hours a night.
In 1777 Marat moved to France, and was fortunate to receive employment as personal physician to the future King Charles X. He quickly established his reputation as an excellent doctor and he moved in court circles as a prominent figure of the medical profession. Enjoying a lavish income, he set up his own laboratory so he could experiment with light, electricity and heat. The scientific establishment in Paris snubbed his work because they did not approve of his experimental methods, although he drew the admiration of some, including Benjamin Franklin.
In 1788, the Third Estate was pushed to the limit and the French Revolution began. Marat completely abandoned medicine and philosophy and focused all his energies upon politics. He resigned from all of his court physician’s duties and never saw a patient again. There was much support for the English system of constitutional monarchy and Marat wrote pamphlets of his experiences of the English system in an attempt to change the direction of the revolution. A tough republican, Marat was still totally against the idea of monarchy in any form.
During the trial of King Louis XVI, Marat argued on an ex post facto basis that he cannot be held guilty for crimes committed before the ratification of the new French constitution. This solitary stance coupled with the continuing attacks from his paper, made Marat an object of hate by members from all sides of the house. In public however, he was seen as a hero who stood up for the working classes and represented the everyday Frenchman.
During this later period of his life Marat was ravaged by a skin disease of uncertain origin. It was intensely pruritic and blistering in nature and caused considerable discomfort. Scarring and disfigurement followed and not long before his death people avoided meeting Marat as a result. Using medicinal baths for relief, Marat, eventually, did most of his writing and other work in the bathroom. It is believed that he contracted the disease while hiding in the Parisian sewers and catacombs. The exact nature of this affliction remains a matter of debate.
While he was taking a medicinal bath on July 13, 1793, Charlotte Corday, a messenger from Caen, arrived at Marat’s home with a report that a Girondin faction was being established in Normandy. Enraged, Marat demanded the names of those responsible and proclaimed “they shall all be guillotined”. At this, Corday stabbed Marat in the chest with a hidden blade. Pierced between the first and second ribs, through the heart and lungs, he died almost instantaneously. Corday was a Girondin who came from a royalist family and had written earlier in the day of her intention to kill “the savage beast fattened on the blood of Frenchmen”. During her trial she argued that she “had killed one man to save a hundred thousand”. Corday was guillotined and throughout France thousands of Girondins were rounded up and executed.
Marat received a full state funeral and for a period of time, the town of L’Havre was renamed Havre-Marat. The acclaimed painter, Jacques-Louis David, himself a member of the convention, was in charge of the ceremony and painted the masterpiece “Marat a son dernier soupir’ (The Death of Marat). In this portrait Marat is captured as a youthful and athletic figure without his skin blemishes. It shows him as a patriot murdered in his bath, while the assassin is conspicuously absent. This was done, to focus the attention on Marat’s “sacrifice,” and not on his murderer. As a politician Marat was directly responsible for mass executions and spent much of his time launching personal attacks on those in power. As a physician he is remembered for the kind treatment he delivered to the people of London, Newcastle and Paris and as a patient he is remembered as one who suffered considerably.
Impaired Clearance, Not Overproduction of Toxic Proteins, May Underlie Alzheimer’s Disease
Alzheimer’s disease (AD) is the most common cause of dementia in older adults, and affects as many as 5.1 million Americans. In the late-onset type of AD, symptoms usually appear after age 65. Many believe that accumulation of abnormal levels of beta-amyloid in the brain initiates a cascade of events leading to the death of brain cells and ultimately to dementia. In the rare, early-onset forms of AD that are linked to genetic mutations there is a marked increase in beta-amyloid production. In the more common, late-onset form of AD, the mechanisms leading to increased beta-amyloid levels are not well understood.
In AD, a protein fragment called beta-amyloid accumulates at abnormally high levels in the brain. According to an article published online in Science (9 December 2010) researchers funded by the National Institutes of Health have found that in the most common, late-onset form of AD, beta-amyloid is produced in the brain at a normal rate but is not cleared, or removed from the brain, efficiently. In addition to improving the understanding of what pathways are most important in development of AD pathology, these findings may one day lead to improved biomarker measures for early diagnosis as well as a new approach to treating this devastating disorder.
Prior studies in animals suggest several possible explanations for the slower clearance of beta-amyloid in late-onset AD. One possibility is that as beta-amyloid accumulates, it acts as a sink for more of the protein, trapping it within the brain. The authors believe that sorting out these mechanisms is likely to help speed the development of new drugs for the disease.
The authors previously reported an innovative procedure to measure beta-amyloid levels over time in cerebrospinal fluid (CSF) – the fluid that bathes the brain. In the new study, the authors measured beta-amyloid levels in the CSF of 12 patients with late-onset AD and 12 cognitively normal individuals. The participants’ average age was 74. Their CSF was sampled every hour for 36 hours, via a one-time lumbar puncture. During the first nine hours, the participants received an IV drip containing leucine, a protein building block, which had been labeled with a non-radioactive isotope. By measuring the amount of labeled beta-amyloid by mass spectroscopy over time, the authors were able to calculate how fast it was produced in the participants’ brains and how fast it was cleared. Results showed that the clearance of beta-amyloid was about 30% slower in individuals with AD than in cognitively normal individuals. This is consistent with previous findings that beta-amyloid is decreased in the CSF of people with AD and in those with mild cognitive impairment at high risk of developing the disease.
The Origin of the Haitian Cholera Outbreak Strain
Although cholera has been present in Latin America since 1991, it had not been epidemic in Haiti for at least 100 years. Recently, however, there has been a severe outbreak of cholera in Haiti. A study published online in the New England Journal of Medicine (9 December 2010) has now identified the origin of the bacterial strain of Vibreo cholera responsible for the Haitian cholera outbreak.
The study used a third-generation single-molecule real-time DNA sequencing to determine the genome sequences of 2 clinical V. cholerae isolates from the current outbreak in Haiti as well as one strain that caused cholera in Latin America in 1991, and two strains isolated in South Asia in 2002 and 2008. Using primary sequence data, the authors compared the genomes of these five strains and a set of previously obtained partial genomic sequences of 23 diverse strains of V. cholerae to assess the likely origin of the cholera outbreak in Haiti.
Results showed that both single-nucleotide variations and the presence and structure of hypervariable chromosomal elements indicated that there is a close relationship between the Haitian isolates and the variant V. cholerae El Tor O1 strains isolated in Bangladesh in 2002 and 2008. In contrast, analysis of genomic variation of the Haitian isolates revealed a more distant relationship with circulating South American isolates.
According to the authors, the Haitian epidemic is probably the result of the introduction, through human activity, of a V. cholerae strain from a distant geographic source.
Effect of Daily Aspirin on Long-Term Risk of Death Due To Cancer
It has been reported that treatment with daily aspirin for 5 years or longer reduces subsequent risk of colorectal cancer. Several lines of evidence suggest that aspirin might also reduce risk of other cancers, particularly of the gastrointestinal tract, but proof is lacking. According to an article published online in the Lancet (7 December 2010), deaths due to cancer were studied during and after randomized trials of daily aspirin versus control done originally for prevention of vascular events.
The study used individual patient data from all randomized trials of daily aspirin versus no aspirin, with mean duration of scheduled trial treatment of 4 years or longer, to determine the effect of allocation to aspirin on risk of cancer death in relation to scheduled duration of trial treatment for gastrointestinal and non-gastrointestinal cancers. In three large UK trials, long-term post-trial follow-up of individual patients was obtained from death certificates and cancer registries.
Results showed that in eight eligible trials (25,570 patients, 674 cancer deaths), allocation to aspirin reduced death due to cancer 21%, p=0.003). On analysis of individual patient data, which were available from seven trials (23,535 patients, 657 cancer deaths), benefit was apparent only after 5 years’ follow-up (all cancers, hazard ratio [HR] 0·66; gastrointestinal cancers, 0·46; both p=0.003). The 20-year risk of cancer death (1,634 deaths in 12,659 patients in three trials) remained lower in the aspirin groups than in the control groups (all solid cancers, HR 0.80, p<0.0001; gastrointestinal cancers, 0·65, p<0.0001). The latent period before an effect on deaths was about 5 years for esophageal, pancreatic, brain, and lung cancer, but was more delayed for stomach, colorectal, and prostate cancer. For lung and esophageal cancer, benefit was confined to adenocarcinomas, and the overall effect on 20-year risk of cancer death was greatest for adenocarcinomas (HR 0.66, p<0·0001). Benefit was unrelated to aspirin dose (75 mg upwards), gender, or smoking, but increased with age – the absolute reduction in 20-year risk of cancer death reaching 7.08% at age 65 years and older.
According to the authors, daily aspirin reduced deaths due to several common cancers during and after the trials. Benefit increased with duration of treatment and was consistent across the different study populations. These findings have implications for guidelines on use of aspirin and for understanding of carcinogenesis and its susceptibility to drug intervention.
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FDA Issues Guidance on Public Comment Procedures at Advisory Committee Meetings
Advisory committees enhance the FDA’s ability to protect and promote public health by ensuring FDA has access to comments from the public through the public hearing process provided in existing laws and regulations. Each advisory committee meeting includes a comment period during which members of the public; individuals or spokespersons from the regulated industry (except the sponsor whose product is under review); consumer advocacy groups; and professional organizations, societies, or organizations are invited to speak.
The FDA has issued final guidance for people who wish to comment during the agency’s advisory committee meetings. The guidance provides instructions on how to request a time to speak and how FDA staff should respond to requests to speak at the meetings.
The FDA encourages participation from all stakeholders in its decision-making process. Every advisory committee meeting includes an open public hearing session, during which interested people may present relevant information or their oral and/or written views.
The guidance finalizes information contained in the 2005 draft guidance titled The Open Public Hearing – FDA Advisory Committee Meetings – Draft Guidance.
Highlights of the guidance include:
- Before an advisory committee meeting, people may ask, either orally or in writing, to speak at the meeting; they should include contact information, topic to discuss, time requested; FDA usually allots 5-10 minutes per person.
- FDA staff responds to requests and, if the topic is unrelated to the committee’s work, may decline the request.
- At the meeting, speakers should identify themselves to FDA staff and provide any handouts or other materials, which staff then provides to committee members. These materials then become part of the meeting’s permanent record.
- Committee members are encouraged to ask questions of the speakers, to discover more information that might be useful to the committee’s deliberations. Committee members and the public should be reminded of the importance of the open public hearing session and that all speakers should be treated with courtesy and respect.
- Public speakers are encouraged to disclose any financial relationships they may have with the topic of the meeting or with sponsors of competitors of the products under discussion.
- FDA will provide a designated seating area for speakers.
Since meetings typically take several months to plan, FDA is implementing the new guidance starting with meetings held in March 2011.