Target Health ( 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, Management of Clinical Trials, Biostatistics, Data Management, EDC utilizing Target e*CRF®, Project Management, 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 checks), 2) Target e*CTMSTM, 3) Target Document®, 4) Target Encoder®, 5) Target Newsletter®, 6) Target e*CTRTM (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.

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner, August 13, 2009, by Todd Neale — If current trends continue, the nation’s aging population will face a shortage of cardiothoracic surgeons by 2025, researchers predict.

Assuming today’s patterns of healthcare use and delivery remain the same, a rapid increase in the 65-and-older population segment will increase demand for cardiothoracic surgery by 46% over the next 15 years, according to Irving Kron, MD, of the University of Virginia in Charlottesville, and colleagues.

At the same time, the supply of surgeons is expected to decline by 21% because of retirements and a declining interest among young doctors in cardiothoracic surgery fellowships, they reported online in Circulation: Journal of the American Heart Association.

The only combination scenario that could forestall such a shortage would involve a current surplus of surgeons, the elimination of coronary artery bypass grafting entirely, and an increase in the number of thoracic surgery trainees, the researchers said.

With each of those scenarios extremely unlikely, “by 2025, it is probable that there will be a shortage of at least 1,500 surgeons or 25% of the likely projected need,” they said.

The shortage could produce poorer patient outcomes “if non-board-certified physicians expand their role in cardiothoracic surgery or patients must delay appropriate care because of a shortage of well-trained surgeons,” they wrote.

Dr. Kron and colleagues derived their findings from a model incorporating population trends and current healthcare use from a variety of data sources.

The proportion of the population 65 and older in the U.S. is expected to swell rapidly from 13% to 20% by 2030, according to a U.S. Census Bureau report. (See World’s Population Grows Increasingly Long in the Tooth)

Unfortunately, the resulting increase in demand for the services of cardiothoracic surgeons from this aging population appears to be accompanied by declining interest in the specialty.

“In 2007,” Dr. Kron said, “33% of available thoracic surgery fellowship positions went unfilled in the National Resident Matching Program.”

One reason for the waning interest could be the decreasing popularity of CABG procedures — which declined by 28% from 1997 to 2004 — and the growing use of stenting, which increased by 121% over the same time period.

Exacerbating the problem is an aging population of cardiothoracic surgeons: more than half are at least 55 and nearing retirement, the researchers said.

Only one-third of physicians overall have reached that age.

Because they require more postgraduate training than most other specialties (an average of 8.3 years), the researchers said, efforts to increase the workforce to sufficient levels by 2025 would have to start today.

The researchers acknowledged some limitations of the analysis, including the uncertainty of how new technology and reimbursement practices will affect trends, and how surgical productivity will change. There were also limitations in the physician supply data and in the assumption that supply and demand were the same at baseline.

The study was funded by American Association for Thoracic Surgery and the Society of Thoracic Surgeons.

The authors made no financial disclosures.
Primary source: Circulation: Journal of the American Heart Association
Source reference:
Grover A, et al “Shortage of cardiothoracic surgeons is likely by 2020” Circulation 2009; DOI: 10.1161/CIRCULATIONAHA.108.776278.,, August 12, 2009, by Lois Romano  —  Van Jones may have one of the hottest assignments in the Obama administration — selling the notion of a new “green-collar” economy — but in a country burdened with a 9.4 percent unemployment rate, it’s not easy.

How do you tell an unemployed construction worker that it’s time to start thinking about installing solar panels instead of aluminum siding? “I think some of these ideas are complicated for people when they first hear them,” said Jones, senior green jobs adviser to the White House Council on Environmental Quality. Most people “don’t know what retrofitting a building means, or they haven’t heard of . . . a smart biofuel. And so a lot of times, people just sort of go yes, yes, but they aren’t really following you.”

Jones, 40, has been a leader in a growing movement that aims to hit two major social and policy challenges — the struggling economy and environmental quality — with one boulder. It’s a vision that has been embraced by various industries and advocacy groups intrigued by the promise of thousands of new green jobs as the country invests in energy efficiency and confronts climate change.

But skeptics say the reality of creating a “green economy” is more complex. As with any new business, start-up costs are high — and money is tight these days. And although the administration has allocated as much as $80 billion through the stimulus package to create more than 6 million green jobs, it is impossible at this point to quantify success. For one, there is no official federal definition of a green job — though the president’s budget includes money for the Bureau of Labor Statistics to work with other agencies to define the green economy and produce data on green-collar jobs by 2011.

Jones said anecdotal evidence is strong that the strategy is working, and he dismissed as “myth” reports that the plan merely moves jobs around the economy without creating new ones. “If you get people in on the ground floor of a growing industry, they can grow that industry,” he said.

His career path was not unlike President Obama’s. After graduating from Yale Law School, Jones worked as a community activist in Oakland, Calif., and founded the Ella Barker Center for Human Rights. A few years ago, he saw an opportunity to combine his commitment to racial and economic parity with work to solve the environmental crisis. He soon became a hero of the green movement as he talked about “greening the ghetto,” appearing on hip shows such as “The Colbert Report” and sending out his message on YouTube.

“I think sometimes when we think about ecological solutions, we think about very high-end stuff — you know, maybe space-age technology, way off in the future,” he said. “What we forget is most of the things we need right now to reduce pollution, to reduce greenhouse gas emissions, don’t require fancy technology. You know what it requires? A caulking gun.”

He launched a Green-Collar Jobs Campaign, which led in 2007 to Green for All, an organization he founded to help create and find jobs in the green economy for the poor and disadvantaged. “People need to have the opportunity to be a part of industries that are going someplace,” he said in an interview at his office across the street from the White House.

“When you’re working in communities where people don’t have a lot of hope for opportunity, you say, geez, [do you] you want to fight, but hard, to get people jobs that you know are going to be dead-end, or can you find them a job in a part of the economy that’s going someplace? . . . And so then I saw that these firms were going places, that’s when I got totally jazzed.”

White House Green Czar, Van Jones, Tells About the US Green Economy

Like Burrs On Your Clothes, Molecule-size Capsules Can Deliver Drugs By Sticking To Targeted Cells


Cornell University (2009, August 11). Like Burrs On Your Clothes, Molecule-size Capsules Can Deliver Drugs By Sticking To Targeted Cells, ScienceDaily. – It is now possible to engineer tiny containers the size of a virus to deliver drugs and other materials with almost 100 percent efficiency to targeted cells in the bloodstream.


According to a new Cornell study, the technique could one day be used to deliver vaccines, drugs or genetic material to treat cancer and blood and immunological disorders. The research is published in the journal Gene Therapy.

“This study greatly extends the range of therapies,” said Michael King, Cornell associate professor of biomedical engineering, who co-authored the study with lead author Zhong Huang, a former Cornell research associate who is now an assistant professor at the Shenzhen University School of Medicine in China. “We can introduce just about any drug or genetic material that can be encapsulated, and it is delivered to any circulating cells that are specifically targeted,” King added.


The technique involves filling the tiny lipid containers, or nanoscale capsules, with a molecular cargo and coating the capsules with adhesive proteins called selectins that specifically bind to target cells. A shunt coated with the capsules is then inserted between a vein and an artery. Much as burrs attach to clothing in a field, the selectin-coated capsules adhere to targeted cells in the bloodstream.


After rolling along the shunt wall, the cells break free from the wall with the capsules still attached and ingest their contents.


The technique mimics a natural immune response that occurs during inflammation, which stimulates cells on blood vessel walls to express selectins, which quickly form adhesive bonds with passing white blood cells. The white blood cells then stick to the selectins and roll along the vessel wall before leaving the bloodstream to fight disease or infection.


Selectin proteins may be used to specifically target nucleated (cells with a nucleus) cells in the bloodstream.


The study shows that since only the targeted cells ingest the contents of the nanocapsules, the technique could greatly reduce the adverse side effects caused by some drugs.


In a previous paper, King showed how metastasizing cancer cells circulating in the blood stream can stick to selectin-coated devices containing a second protein that programs cancer cells to self-destruct.


Said King, “We’ve found a way to disable the function of cancer cells without compromising the immune system,” which is a problem with many other therapies directed against metastasis.


The current study demonstrates that genetic material can be delivered to targeted cells to turn off specific genes and interfere with processes that lead to disease. The researchers filled nanocapsules with a small-interfering RNA (siRNA) and targeted them to specific circulating cells. When the targeted cells ingested the capsules, the siRNA turned off a gene that produces an enzyme that contributes to the degradation of cartilage in arthritis.


In a similar manner, the method could be used to target the delivery of chemotherapy drugs, vaccine antigens to white blood cells, specific molecules that mitigate auto-immune disorders and more, King said.


Journal reference:

•1.                  Huang et al. An immobilized nanoparticle-based platform for efficient gene knockdown of targeted cells in the circulation. Gene Therapy, Online June 25, 2009; DOI: 10.1038/gt.2009.76

Adapted from materials provided by Cornell University. 

Study Shows High Total Cholesterol in Midlife Could Raise Risk for Alzheimer’s Disease

Reviewed by Elizabeth Klodas, MD, FACC, Aug. 12, 2009, by Salynn Boyles — Adults with even moderately elevated cholesterol in their early to mid-40s appear to have an increased risk for Alzheimer’s disease and related dementias decades later, a new study shows.

Researchers followed more than 9,800 people for four decades in one of the largest and longest age-related dementia trials ever conducted.

They found that those with high or even borderline high total cholesterol in their 40s had a significantly increased risk for developing Alzheimer’s disease years later.

“People tend to think of the brain and the heart as totally separate, but they are not,” study co-author Rachel A. Whitmer, PhD of Kaiser Permanente Division of Research in Oakland, Calif., tells WebMD. “We are learning that what is good for the heart is also good for the brain — and that midlife is not too soon to be thinking about risk factors for dementia.”

Cholesterol and Alzheimer’s Disease

The study included 9,844 northern California residents enrolled in the same health insurance plan throughout the study.

Close to 600 had developed either Alzheimer’s disease or a related condition known as vascular dementia by the end of the study, when they were in their 60s, 70s, and 80s.

Total cholesterol in the high range at study entry was associated with a 66% increase in Alzheimer’s risk, while having borderline high cholesterol raised the risk for vascular dementia by 52%.

According to current guidelines, total cholesterol of 240 or higher is considered high, and a cholesterol of 200 to 239 is considered borderline high.

The researchers did not have information on HDL “good” and LDL “bad” cholesterol because the significance of these different types of lipids was not widely understood four decades ago.

But it is safe to assume that most people whose total cholesterol was high had high levels of bad cholesterol because about two-thirds of total cholesterol reflects LDL, Whitmer says.

Good for Heart, Good for Brain

The study, conducted by researchers with Kaiser and Finland’s University of Kuopio, is one of the first to examine risk for vascular dementia, a group of dementia syndromes associated with reduced blood supply to the brain.

Lead author Alina Solomon, MD, of the University of Kuopio tells WebMD that the study adds to the growing evidence that controlling heart disease risk factors like cholesterol, blood pressure, diabetes, and weight in midlife can protect the brain in old age.

“Keeping your weight down, eating right, and getting regular exercise can keep your heart healthy as you age, and it may also keep your brain sharp,” she says.

Alzheimer’s Association Chief Medical and Scientific Officer William H. Thies, PhD, agrees that it is increasingly clear that lifestyle influences risk, even among people who have a genetic predisposition for developing late-life dementias.

“We can’t really say how much of risk is lifestyle and how much is genetic,” he says. “We know that most patients with Alzheimer’s also have vascular disease and that the risk factors for vascular disease are modifiable with lifestyle.”

Making Changes to Lower Risk

Computer specialist James Pitman, 44, has gotten the message and is making lifestyle changes to bring his high cholesterol down in hopes of reducing his risk for heart disease, diabetes, and dementia later in life.

The Oakland, Calif., resident, who has a family history of diabetes and Alzheimer’s disease, has lowered his total cholesterol from 280 to 260 by eating better and revamping his exercise routine. He tells WebMD that he hopes to lower his numbers more by making additional changes.

“I didn’t exactly win the genetic lottery, so I will probably have to go on drugs eventually to lower my cholesterol,” he says. “But I am going to do all I can with diet and exercise.”


Wednesday, Aug. 12, 2009                                  

NIAID Scientists View Past Flu Pandemics for Clues to Future Course of 2009 H1N1 Virus

Flu Viruses Notoriously Unpredictable; Robust Pandemic Preparedness Efforts Crucial


A commonly held belief that severe influenza pandemics are preceded by a milder wave of illness arose because some accounts of the devastating flu pandemic of 1918-19 suggested that it may have followed such a pattern. But two scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, say the existing data are insufficient to conclude decisively that the 1918-19 pandemic was presaged by a mild, so-called spring wave, or that the responsible virus had increased in lethality between the beginning and end of 1918. Moreover, their analysis of 14 global or regional influenza epidemics during the past 500 years reveals no consistent pattern of wave-like surges of disease prior to the major outbreaks, but does point to a great diversity of severity among those pandemics.

In their commentary in the Aug. 12 issue of the Journal of the American Medical Association, David M. Morens, M.D., and Jeffery K. Taubenberger, M.D., Ph.D., note that the two other flu pandemics of the 20th century, those of 1957 and 1968, generally showed no more than a single seasonal recurrence; and in each case, the causative virus did not become significantly more pathogenic over the early years of its circulation.

The variable track record of past flu pandemics makes predicting the future course of 2009 H1N1 virus, which first emerged in the Northern Hemisphere in the spring of 2009, difficult. The authors contend that characteristics of the novel H1N1 virus, such as its modest transmission efficiency, and the possibility that some people have a degree of pre-existing immunity give cause to hope for a more indolent pandemic course and fewer deaths than in many past pandemics.

Still, the authors urge that the 2009 H1N1 virus continue to be closely tracked and studied as the usual influenza season in the Northern Hemisphere draws near. Like life, the authors conclude, paraphrasing Danish philosopher Soren Kierkegaard, “influenza epidemics are lived forward and understood backward.” Thus, the robust, ongoing efforts to meet the return of 2009 H1N1 virus with vaccines and other measures are essential responses to a notoriously unpredictable virus.

ARTICLE:   DM Morens and JK Taubenberger. Understanding influenza backward. Journal of the American Medical Association 302: 679-80. DOI: 10.1001/jama.302.6.679 (2009).


China has become a huge supplier of drug and device components and finished products – and associated quality problems have made headlines worldwide. If you are considering or already using a Chinese supplier, what can you do to research the company — and not end up a headline yourself?

Here’s a terrific resource you may not have considered: Let FDA help you do your research!


Any Chinese firm exporting medical products to the US is subject to FDA inspection, and the resulting Establishment Inspection Reports (EIRs) and 483s give an insider’s look at a plant: the history of the firm, the names of the top executives, a description of their operations, and, of course, the FDA Investigator’s assessment of their conformance to quality regulations. Finally, the EIR includes a “Discussion with Management” that, when read carefully, can give you real insight into the personality of the firm and management’s attitude to and comprehension of FDA regulations. FDA doesn’t put these EIRs and 483s on their own website. But by using the Freedom of Information Act, FOI Services has built up a good collection of these revealing documents for you to download on the spot.


Have a look right now! We’ve put together a sampling of document descriptions for our bestselling Chinese EIRs and 483s – just go to our home page at and click on the Chinese flag in the left hand column. Be sure to look over each entry – we’ve included a typical EIR for you to download at no charge!


Researching Chinese firms is notoriously difficult: save yourself time, frustration, and potentially devastating quality problems – take advantage of the documents your competitors have found extremely valuable in their own due diligence.


As always, if you’d like help finding or ordering a document, you are welcome to call at +1-301-975-9400; our information specialists are here to assist you.


Search & download unpublished FDA documents acquired under the Freedom of Information Act,
browse hot topics, and learn from teleconferences by leading regulatory experts

The FOI Online library consists of over 118,000 drug, device, and other FDA related documents. Click on a document type below for a detailed description and sample document pages. 

For Examples of Chinese Inspection Reports Available, Take a Look Below


  • Changzhou Pharmaceutical Factory

Jiangsu, China
October 28-31, 2002
FDA Investigators: Horan, Robert; Szestypalow, Kathy
Size of 483: 3 pages
Products: Unspecified pharmaceutical products

Pre-approval cGMP inspection of API manufacturing facility. Observations include an employee cleaning equipment in a controlled area while wearing a band-aid and no other hand covering. Document contains the firm’s well-written, point-by-point response to the 483.

Order No. 5221674A – $89.95 per copy


  • Shanghai Medicinal Factory #15

Shanghai, China
October 27-31, 2003
FDA Investigators: Horan, Robert; Ting, Susan
Size of 483: 3 pages
Products: Unspecified pharmaceutical and veterinary products

For cause inspection initiated as a cGMP inspection covering all products made at this facility. The firm’s compliance status was OAI (Official Action Indicated) following an inspection the previous year. This 2003 follow-up inspection found significant data integrity problems, as well as several cGMP deficiencies. A separate section of the EIR was dedicated to the data integrity concerns, which left the investigators with the feeling that they “did not have confidence in the integrity of any of the data” they were examining. It is noted that evidence of deliberate data misrepresentation was found. The EIR also noted that a plant manager apologized for management “not having been truthful”. A copy of the company’s response to the 483 (which denies any deliberate wrongdoing) is included, along with the Warning Letter and subsequent correspondence.

Order No. 5214261F – $89.95 per copy



  • Delta Synthetic

Taiwan, China
October 27-29, 2003
FDA Investigators: Flynn, George;
Needham, Richard
Size of 483: 3 pages
Products: Unspecified Drug Master File (DMF)

Pre-approval inspection was prompted by an unspecified NDA and an unspecified ANDA. The 483 lists 21 deficiencies, including an observation that none of the manufacturing equipment had been qualified. Also included in the file are the firm’s response to the 483 and a Warning Letter issued after receipt of the 483 response to the FDA.

Order No. 5218629B – $89.95 per copy


  • Suzhou No.4 Pharmaceutical Factory

Suzhou, China
March 29 –
April 1, 2004
FDA Investigators: Flynn, George;
Needham, Richard
Size of 483: 3 pages
Products: Unspecified ANDA & DMF

Inspection of Active Pharmaceutical Ingredient (API) manufacturer assigned under Compliance Programs 7352.832 and 7356.002F. This inspection resulted in a recommendation for an unacceptable classification for the facility. Twelve deficiencies were noted regarding validation, instrument calibration, and impurity profile data as well as other areas. The firm’s response is included.

Order No. 5203873A – $89.95 per copy



  • Syntec Scientific

Chang Hua, Taiwan, China
May 2-5, 2005
FDA Investigator: Masley-Joseph, Karen
Size of 483: 3 pages
Products: Non-sterile orthopedic screws and plates

Inspection of medical device manufacturer which covered the firm’s MDR practices, Management Controls, Design Controls, CAPA, and Production and Process Controls. Observations included a lack of documentation for disposition of nonconforming or returned product and a lack of written procedures for reporting MDRs to FDA.

Order No. 5237276B – $69.95 per copy


  • Huadong Medicine

Hangzhou, China
October 17-20, 2005
FDA Investigator: Leonin, Paraluman
Size of 483: 2 pages
Products: Unspecified ANDA

Initial inspection of Active Pharmaceutical Ingredient (API) manufacturer, which served as a pre-approval inspection for an unspecified ANDA product. The firm was deemed acceptable to manufacture, but notable deficiencies regarding documentation and SOPs were cited. In particular, the SOP for an unidentified system is said to have given no guidance as to “what should be done when any of the parameters used to monitor the system is out of specification”.

Order No. 5237223A – no charge per copy


  • Leshan Saniju- Long March Pharmaceuticals

Sichaun, China
October 21-25, 2002
FDA Investigators: Faul, Kent; Horan, Robert; McReavey, James; Szestypalow, Katherine
Size of 483: 1 page
Products: Gentamicin Sulfate, Oxytetracycline

This was a follow-up inspection due to the firm being under an import alert for human and veterinary products. The import alert had been prompted after a 1999 inspection raised concerns involving data integrity and significant cGMP deficiencies. Following the 1999 inspection, the firm underwent ownership and management changes and improved the manufacturing system. Based on the previous inspection, much of this 2002 inspection focused on the impurity profile for gentamicin sulfate. Though only relatively minor observations were noted on the 483, and none regarding gentamicin sulfate, the investigators remained concerned “regarding the ability of the firm’s method to achieve adequate resolution and quantitation of certain impurities”. As noted in subsequent correspondence, the firm was recommended as acceptable for manufacture of APIs with the exception of gentamicin sulfate. Leshan Saniju-Long March’s response to the 483 is included.

Order No. 5210835A – $89.95 per copy


  • Chongqing Daxin Pharmaceutical

Chongqing, China
September 24-25, 2001
FDA Investigators: Edwards, Charles; Henry, Yvette
Size of 483: 1 page
Products: Unspecified Active Pharmaceutical Ingredient (API) products

Here’s an example of an inspection that went well. This was a GMP Qualifying Inspection done in accordance with CP 7356.002F. Though four observations were noted, the firm’s corrections were already noted on the 483 when it was prepared.

Order No. 5217242B – $69.95 per copy


  • Huzhou Zhanwang Chemical Pharmaceutical

Huzhou, Zhejiang, China
October 31 –
November 3, 2005
FDA Investigator: Paraluman, Leonin
Size of 483: 1 page
Products: Unspecified ANDAs

Pre-approval and cGMP inspection of Active Pharmaceutical Ingredient (API) manufacturer. Two significant observations regarding documentation and incomplete laboratory records were noted, and two non-483 findings were also discussed with management. Following the inspection and the firm’s response to the 483, FDA emphasized that the firms’ corrective actions would be further evaluated at the next inspection.

Order No. 5238172C – $89.95 per copy


  • Tianjin Xin Xin Pharmaceutical

Tianjin, China
September 4-7, 2000
FDA Investigators: Campbell, Karyn; Laska, Susan; Ting, Susan
Size of 483: 4 pages
Products: Unspecified Active Pharmaceutical Ingredients (APIs)

Follow-up compliance inspection following February 2000 Warning Letter and Import Alert that resulted from a prior inspection. This current inspection resulted in recommendations for a continued Import Alert and an Untitled Letter. Significant findings involving incomplete process validation were noted and previous objectionable conditions were found not to have been corrected sufficiently. One example is the firm’s investigation into previously returned lots, which were returned due to metallic particles. Investigators found that no attempt had been made to ensure prevention of future occurrences. File includes Tianjin Xin Xin’s response to the 483, a subsequent, seven-page December 2000 Warning Letter, firm’s response to the Warning Letter, and, finally, FDA’s response which reflects a still-incomplete satisfaction with the firm’s processes.

Order No. 5217486B – $89.95 per copy


  • Jiangsu Heingrui Pharmaceutical

Lianyungang, Jiangsu, China
September 11-13, 2000
FDA Investigators: Campbell, Karyn; Laska, Susan; Ting, Susan
Size of 483: 4 pages
Products: Unspecified Active Pharmaceutical Ingredients (APIs)

Compliance follow-up inspection following a June 2000 Warning Letter. Jiangsu Heingrui’s response to the previous 483 and Warning Letter were deemed “deficient”. At the conclusion of this September 2000 inspection, the firm was still listed as unacceptable for manufacturing APIs. The 21 observations on the 483 include inconsistent impurity analysis, no annual review of records or quality investigations, inadequate process validation and inadequate analytical methods validation. During discussion between management and the investigators, the QC Director admits that “there is no mechanism for quality to be notified or a controlled system for investigations”. A November 2000 Warning Letter was issued after receipt of the firm’s 483 response, requesting an Import Alert. This file includes the 483 response, the November Warning Letter, and the firm’s response to the Warning Letter.

Order No. 5217664B – $89.95 per copy


  • Fujian Fukang Pharmaceutical

Fuzhou, China
March 24-27, 2003
FDA Investigators: Cantellops, Dennis; Flynn, George
Size of 483: 1 page
Products: Gentamicin Sulfate, Chlortetracycline HCl, Chlortetracycline Feed Grade

Inspection of API manufacturer for pharmaceutical and veterinary products conducted in accordance with CP 68001 and CP56002F. The investigators compliment the firm’s preparation for the inspection, but do note 9 deficiencies regarding degradation studies, product annual review, and integrity testing, among other areas.

Order No. 5217325B – $69.95 per copy


  • Xinjiang Pharmaceuticals

Xinjiang, China
September 18-19, 2000
FDA Investigator: Laska, Susan
Size of 483: 1 page
Products: Unspecified Active Pharmaceutical Ingredient (API)

Surveillance GMP inspection. This was the initial inspection of this API manufacturer and revealed that the firm was operating with no process validation, no documentation of investigations into out-of-specification results, no impurity profile, and deficient analytical methods, among other issues. The 483 lists 11 observations. Upon finding the firm’s 483 response inadequate, FDA issued a Warning Letter in December 2000. Both follow-up documents are included in this file.

Order No. 5217485B – $89.95 per copy


  • Tianjin Zhong Xin Pharmaceutical

Tianjin, China
November 17-20, 2003
FDA Investigators: Dickinson, Gwyn; Faul, Kent
Size of 483: 3 pages
Products: Unspecified Active Pharmaceutical Ingredients (APIs)

Pre-approval and cGMP inspection of a firm with a history of significant deficiencies and warning letters. This inspection was a follow-up to a 2000 inspection and Warning Letter. The EIR details the current inspection and findings, as well as a good deal of the previous observations and corrections. Investigators found that most of the 2000 deficiencies had been corrected, and noted the firm’s positive attitude toward compliance, but cited continuing problems with inadequate test methods. No Warning Letter was issued and the firm was declared acceptable for manufacture of the relevant APIs.

Order No. 5214261G – $89.95 per copy


Denosumab Helps Men Undergoing Prostate Cancer Treatment Avoid Fractures,,, August 11, 2009, by John Gever  —  An experimental biologic drug for osteoporosis increased bone density and reduced fractures in men and women in two controlled clinical trials.

Three years of treatment with denosumab reduced radiographic spine fractures more than two-thirds in the randomized FREEDOM study of nearly 7,900 postmenopausal women.

Overall, those fractures appeared in 2.3 percent of the denosumab group, compared with 7.2 percent of patients taking placebo, according to Dr. Steven Cummings of California Pacific Medical Center in San Francisco and colleagues.

And a separate trial by Dr. Matthew Smith of Massachusetts General Hospital in Boston and colleagues documented a similar reduction in new vertebral fractures after two years of denosumab in 1,468 men undergoing androgen-deprivation therapy for prostate cancer, and hence at risk for bone loss.

Both studies were published online in the New England Journal of Medicine. Both sets of researchers reported increases in bone mineral density (BMD) at various body sites with denosumab, whereas no change or decreases in BMD were seen in the placebo groups.

Preliminary results from the two studies were reported last year.

Sundeep Khosla, MD, of the Mayo Clinic in Rochester, Minn., in an accompanying NEJM editorial.Although the drug did not seem to increase infection rates in either study, Khosla noted that its potential to depress immune function remained an issue.

He added that its cost could “considerably limit its use” if it turns out to be much higher than zoledronic acid (Reclast), the bisphosphonate drug that appears to be denosumab’s most direct competitor.

The double-blind, randomized, placebo-controlled study by Cummings and colleagues enrolled 7,868 women 60 to 90 years old with established osteoporosis.

Patients received calcium supplements of at least 1,000 mg/day. Vitamin D supplements were provided as well. No bisphosphonates or other osteoporosis drugs were allowed.

Denosumab was given as an injection every six months for three years. Lateral spine radiographs were taken annually and analyzed at a central facility for new vertebral fractures.

New Drug Appears to Cut Fracture Risk in Men, Women

At the three-year evaluation, the researchers found that the risk for new vertebral fractures detected by imaging in the group taking denosumab are only about one-third of that in those taking placebo. Similar reductions were seen in rates of vertebral fracture cases seen by doctors and the number of cases involving two or more vertebral fractures detected by X-ray. The group receiving denosumab also enjoyed better improved density.

In the other study, involving men with prostate cancer undergoing anti-androgen therapy, the basic pattern of results was similar. As in the FREEDOM trial, the drug was given every six months by injection.

Smith and colleagues found the overall incidence of new vertebral fractures in the study after three years of treatment was 1.5 percent with denosumab versus 3.9 percent among placebo patients.

Adverse effects were largely similar between treatment groups in both studies, though the male patients showed slightly higher rates (34.6 percent versus 30.6 percent for serious events and 5.9 percent versus 4.6 percent for serious events related to infections). But notably absent from the list of adverse events was osteonecrosis of the jaw, a rare but worrisome side effect of bisphosphonate drugs.

Although the data do not rule out the possibility that osteonecrosis could occur with denosumab, it was encouraging to see no cases thus far, Cummings suggested. He said follow-up of FREEDOM participants would continue for 10 years, which may provide a more definitive view of the risk.

Denosumab’s manufacturer, Amgen, has not yet announced the pricing for the drug. Nevertheless, as a biologic drug, denosumab is widely expected to be relatively expensive.

But another academic specialist contacted by MedPage Today and ABC News suggested a higher price could be acceptable given denosumab’s potential advantages.

Endocrinologist Dr. Roberto Pacifici of Emory University in Atlanta said the “number needed to treat” in preventing fractures has been low in the denosumab studies reported to date.

The Question of Cost

“Therefore the cost of the drug is likely to be [worthwhile] in many patients,” he said. “Guidelines will have to be developed in order to use this agent in the most cost-effective way.”

Cummings said that if the drug is approved, he would consider it primarily for patients with a poor history on bisphosphonates.

“Those who have had trouble with oral drugs,” because of side effects or compliance problems, would be the main candidates for denosumab, he said.

Another point in denosumab’s favor, Cummings said, is that it is less persistent in bone than many bisphosphonates, making its activity potentially reversible  an important point for patients experiencing adverse effects.

In addition, Dr. Khosla pointed out, “since bisphosphonates are cleared by the kidney and contraindicated in patients with renal insufficiency, denosumab (which is cleared by nonrenal metabolism) may prove to be a safe drug in these patients, although studies that directly address this issue need to be done.”

Amgen filed last December for FDA approval of the agent for treatment and prevention of postmenopausal osteoporosis in women and treatment and prevention of bone loss in patients undergoing hormone ablation therapy for either prostate or breast cancer. The two trials were funded by Amgen.

This article was developed in collaboration with ABC News.

20090812-7, August 11, 2009 (PRNews)  Twice-Yearly Administration of Denosumab Resulted in 68 Percent Reduction in Risk for a Vertebral Fracture and 40 Percent Reduction in Risk for a Hip Fracture in Women with Postmenopausal Osteoporosis

Denosumab Administered Twice-Yearly Reduced the Incidence of New Vertebral Fractures by 62 Percent in Men with Non-Metastatic Prostate Cancer Undergoing Androgen Deprivation Therapy

THOUSAND OAKS, Calif., Aug. 11 /PRNewswire-FirstCall/ — Amgen Inc. (Nasdaq: AMGN) today announced the publication of results from two pivotal Phase 3 studies investigating the safety and effectiveness of denosumab at reducing fracture risk in more than 7,800 women with postmenopausal osteoporosis and in more than 1,400 men with non-metastatic prostate cancer undergoing androgen deprivation therapy (ADT) leading to bone loss. In both studies, published today in The New England Journal of Medicine (NEJM), patients receiving twice-yearly denosumab experienced significant increases in bone mineral density (BMD) compared to placebo, associated with more than 60 percent reduction in vertebral fracture in both patient populations.(1,2) These data were previously reported by Amgen at medical congresses.

To view the Multimedia News Release, go to:

“The discovery of the RANK Ligand pathway represents a significant advance in the understanding of bone biology,” said Roland Baron, Ph.D., D.D.S., professor and chair of department of Oral Medicine, Infection, and Immunity at the Harvard School of Dental Medicine. “These results demonstrate that targeting the RANK Ligand pathway with denosumab could represent a promising new approach in two different disease settings characterized by bone loss.”

FREEDOM Osteoporosis Study Results: Significant Fracture Reduction Seen Across the Skeleton in Postmenopausal Women with Osteoporosis

Results from the FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every six Months) study, showed that women receiving a subcutaneous shot of denosumab twice-yearly experienced a 68 percent reduction in the risk of suffering a vertebral (spine) fracture compared to those receiving placebo as well as a 40 percent reduction in the risk of suffering a hip fracture and a 20 percent reduction in the risk of suffering a nonvertebral fracture. Over the three years of this multi-center, randomized, double-blind, placebo-controlled study, women treated with denosumab experienced significant increases in BMD (8.8 percent at the lumbar spine and 6.4 percent at the total hip).(1)

“These results suggest that denosumab offers a new approach to prevention of fractures in women with postmenopausal osteoporosis,” said Steven Cummings M.D., lead investigator, study author, and director of the San Francisco Coordinating Center of the California Pacific Medical Center Research Institute. “It reduces the risk of all major types of fractures and, because it is given as an injection twice a year, it also has the potential to help compliance to treatment.”

Fracture is one of the most common health events suffered by postmenopausal women with osteoporosis.(3) Globally, one woman in three over 50 years of age will experience a fracture in her lifetime.(3) A woman who has broken a bone as a result of osteoporosis has more than an eight- out-of-ten chance of breaking another bone.(4) Half of women who break a hip, a life changing event, will permanently need assistance to walk.(5)

The overall incidence and type of side effects with denosumab were similar to placebo in the FREEDOM study. Rates of adverse events (AEs) were similar in both groups (93 percent). Rates of serious AEs were 25.8 percent for denosumab and 25.1 percent for placebo. The most common AEs across both treatment arms were arthralgia, back pain, hypertension and nasopharyngitis. There were no reported cases of osteonecrosis of the jaw among patients taking denosumab. Serious adverse events of skin infections, predominantly cellulitis, were reported more commonly in the denosumab group (0.4 percent vs. <0.1 percent). Mild, transient decreases in serum calcium were observed that had no apparent clinical significance.(1)

HALT Study Results: First Published Study to Demonstrate Fracture Prevention in Men with Non-Metastatic Prostate Cancer Undergoing ADT

Results from the HALT (Hormone AbLation Therapy) study in 1,468 men undergoing ADT for non-metastatic prostate cancer show that patients treated with denosumab experienced a 62 percent reduction in the risk of suffering a new vertebral fracture with denosumab compared to placebo at 36 months, with significant reduction observed as early as month-12.(2) Bone loss and increased fracture risk are serious and under-recognized consequences of ADT(6,7) and currently there are no approved therapies for these patients.

In this multi-center, randomized, double-blind, placebo-controlled study, men receiving 60 mg denosumab administered subcutaneously experienced a 6.7 percent increase in BMD at the lumbar spine compared to those receiving placebo (primary endpoint) at 24 months. Increases in BMD at the lumbar spine were observed as early as one month after starting treatment with denosumab and continued to increase throughout the study. In addition, denosumab produced significant increases in BMD at non-vertebral sites (total hip 4.8 percent, femoral neck 3.9 percent, and distal 1/3 radius 5.5 percent), compared to placebo.(2)

“Bone loss and fractures are an important but often unrecognized problem for prostate cancer survivors. Bone loss is an early adverse effect and even short-term androgen deprivation therapy negatively impacts skeletal health. Prevention of bone loss and fractures has been a key unmet medical need for men with prostate cancer,” said Matthew Smith, M.D., Ph.D., study author, associate professor of medicine and the director of Genitourinary Medical Oncology at Massachusetts General Hospital Cancer Center. “In this large international study, denosumab markedly increased bone mineral density and decreased the risk of fractures in many men receiving androgen deprivation therapy for prostate cancer. The efficacy of denosumab was apparent as early as one month and was sustained for three years.”

In the HALT trial, the overall incidence and type of side effects with denosumab were similar to placebo. Rates of AEs were similar in both groups (87 percent). Rates of serious AEs were 35 percent for denosumab and 31 percent for placebo. The most common AEs across both treatment arms were arthralgia, back pain, constipation, pain in extremity, and hypertension. There were no reported cases of osteonecrosis of the jaw among patients treated with denosumab. More patients receiving denosumab developed cataracts, though none were considered treatment-related. One patient in the denosumab arm developed hypocalcemia, versus none in the placebo arm. New primary malignancies were reported in 5 percent of patients in each group. Serious AEs of infections were reported in 6 percent of denosumab-treated patients and in 5 percent of placebo-treated patients.(2)

“Amgen scientists in the 1990s were the first to identify the RANK Ligand pathway, a pivotal physiologic mechanism that controls bone remodeling,” said Roger Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen. “Today’s publications in the New England Journal of Medicine underscore the significance of this finding, and highlight Amgen’s focus on using innovative research to address grievous illness.”

About Denosumab

Denosumab is the first fully human monoclonal antibody in late stage clinical development that specifically targets RANK Ligand, an essential regulator of osteoclasts (the cells that break down bone). Denosumab is being investigated for its potential to inhibit all stages of osteoclast activity through a targeted mechanism. Denosumab is being studied in a range of bone loss conditions including postmenopausal osteoporosis and bone loss in patients undergoing hormone ablation for prostate and breast cancer.

In February 2009, the U.S. Food and Drug Administration (FDA) accepted the Biologics License Application (BLA), submitted by Amgen for denosumab for the treatment and prevention of osteoporosis in postmenopausal women and cancer treatment-induced bone loss in women and men receiving hormone therapy for either breast cancer or prostate cancer based on these studies and a parallel trial in women with breast cancer. The FDA has provisionally approved the trade name Prolia(TM) in these proposed indications, for which denosumab is administered twice yearly subcutaneously at a 60mg dose. The trade name is only for these indications and may not apply for other indications of denosumab.

Amgen has also submitted marketing applications for use of denosumab in the European Union, Canada, Switzerland, and Australia.

Osteoporosis: Impact and Prevalence

Often referred to as the “silent epidemic,” osteoporosis is a global problem that is increasing in significance as the population of the world both increases and ages. The World Health Organization (WHO) has recently identified osteoporosis as a priority health issue along with other major non-communicable diseases.

The economic burden of osteoporosis is comparable to that of other major chronic diseases; for example, in the U.S., the costs associated with osteoporosis-related fractures are equivalent to those of cardiovascular disease and asthma.(8,9,10) It has been reported that osteoporosis results in more hospital bed-days than stroke, myocardial infarction or breast cancer.(11)

Bone Loss Due to Hormone Ablation Therapy

Worldwide, prostate cancer and breast cancer are two of the most frequent types of cancer affecting men and women, respectively.(12) In the U.S., prostate cancer is the most common cancer in men and breast cancer is the most common cancer in women. It is common for prostate cancer and breast cancer patients to receive hormone ablation therapies that can lead to a decrease in bone mass and increased risk of fractures. Currently there are no approved therapies for bone loss in patients undergoing hormone ablation for either prostate or breast cancer.

About Amgen

Amgen discovers, develops, manufactures and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science’s promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis, and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people’s lives. To learn more about our pioneering science and our vital medicines, visit

Forward-Looking Statements

This news release contains forward-looking statements that are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements, including estimates of revenues, operating margins, capital expenditures, cash, other financial metrics, expected legal, arbitration, political, regulatory or clinical results or practices, customer and prescriber patterns or practices, reimbursement activities and outcomes and other such estimates and results. Forward-looking statements involve significant risks and uncertainties, including those discussed below and more fully described in the Securities and Exchange Commission (SEC) reports filed by Amgen, including Amgen’s most recent annual report on Form 10-K and most recent periodic reports on Form 10-Q and Form 8-K. Please refer to Amgen’s most recent Forms 10-K, 10-Q and 8-K for additional information on the uncertainties and risk factors related to our business. Unless otherwise noted, Amgen is providing this information as of Aug. 11, 2009, and expressly disclaims any duty to update information contained in this news release.

No forward-looking statement can be guaranteed and actual results may differ materially from those we project. Discovery or identification of new product candidates or development of new indications for existing products cannot be guaranteed and movement from concept to product is uncertain; consequently, there can be no guarantee that any particular product candidate or development of a new indication for an existing product will be successful and become a commercial product. Further, preclinical results do not guarantee safe and effective performance of product candidates in humans. The complexity of the human body cannot be perfectly, or sometimes, even adequately modeled by computer or cell culture systems or animal models. The length of time that it takes for us to complete clinical trials and obtain regulatory approval for product marketing has in the past varied and we expect similar variability in the future. We develop product candidates internally and through licensing collaborations, partnerships and joint ventures. Product candidates that are derived from relationships may be subject to disputes between the parties or may prove to be not as effective or as safe as we may have believed at the time of entering into such relationship. Also, we or others could identify safety, side effects or manufacturing problems with our products after they are on the market. Our business may be impacted by government investigations, litigation and products liability claims. We depend on third parties for a significant portion of our manufacturing capacity for the supply of certain of our current and future products and limits on supply may constrain sales of certain of our current products and product candidate development.

In addition, sales of our products are affected by the reimbursement policies imposed by third-party payors, including governments, private insurance plans and managed care providers and may be affected by regulatory, clinical and guideline developments and domestic and international trends toward managed care and healthcare cost containment as well as U.S. legislation affecting pharmaceutical pricing and reimbursement. Government and others’ regulations and reimbursement policies may affect the development, usage and pricing of our products. In addition, we compete with other companies with respect to some of our marketed products as well as for the discovery and development of new products. We believe that some of our newer products, product candidates or new indications for existing products, may face competition when and as they are approved and marketed. Our products may compete against products that have lower prices, established reimbursement, superior performance, are easier to administer, or that are otherwise competitive with our products. In addition, while we routinely obtain patents for our products and technology, the protection offered by our patents and patent applications may be challenged, invalidated or circumvented by our competitors and there can be no guarantee of our ability to obtain or maintain patent protection for our products or product candidates. We cannot guarantee that we will be able to produce commercially successful products or maintain the commercial success of our existing products. Our stock price may be affected by actual or perceived market opportunity, competitive position, and success or failure of our products or product candidates. Further, the discovery of significant problems with a product similar to one of our products that implicate an entire class of products could have a material adverse effect on sales of the affected products and on our business and results of operations.

The scientific information discussed in this news release related to our product candidates is preliminary and investigative. Such product candidates are not approved by the U.S. Food and Drug Administration (FDA), and no conclusions can or should be drawn regarding the safety or effectiveness of the product candidates. Only the FDA can determine whether the product candidates are safe and effective for the use(s) being investigated. Further, the scientific information discussed in this news release relating to new indications for our products is preliminary and investigative and is not part of the labeling approved by the U.S. Food and Drug Administration (FDA) for the products. The products are not approved for the investigational use(s) discussed in this news release, and no conclusions can or should be drawn regarding the safety or effectiveness of the products for these uses. Only the FDA can determine whether the products are safe and effective for these uses. Healthcare professionals should refer to and rely upon the FDA-approved labeling for the products, and not the information discussed in this news release.

    CONTACT: Amgen, Thousand Oaks

    Sarah Reines:  (805) 447-9783  (media, osteoporosis)

    Lisa Rooney:  (805) 447-6437  (media, oncology)

    Arvind Sood:  (805) 447-1060  (investors)



  1. Cummings SR, et al. Twice Yearly Denosumab, a Monoclonal Antibody to RANK-ligand, for Prevention of Fractures in Postmenopausal Women with Osteoporosis. N Engl J Med, 2009 Aug. 20; published online at on Aug. 11, 2009.
  2. Smith MR, et al. Denosumab for the Prevention of Bone Loss and Fractures in Men Receiving Androgen Deprivation Therapy in Non-Metastatic Prostate Cancer. N Engl J Med, 2009 Aug. 20; published online at on Aug. 11, 2009.
  3. Melton LJ, et al. (1992) Perspective. How Many Women Have Osteoporosis? J Bone Miner Res, 1992;7:1005
  4. Kanis JA, et al. A Meta-Analysis of Previous Fracture and Subsequent Fracture Risk. Bone, 2004;35:375.
  5. Magaziner J, et al. Predictors of Functional Recovery One Year Following Hospital Discharge for Hip Fracture: A Prospective Study. J Gerontol, 1990;45:M101.
  6. Higano 2008; Higano 2004; Conde 2003; Smith 2001; Pfeilschifter 2000.
  7. Oefelein MG, Ricchiuti V, Conrad W, Resnick MI. Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol. 2002;168:1005-1007.
  8. Burge R, et al. J Bone Miner Res. 2007; 22:465-475
  9. “Osteoporosis Fast Facts.” Washington (DC): National Osteoporosis Foundation. Accessed on February 24, 2009 at
  10. “Economic Cost of Cardiovascular Diseases.” Dallas (TX): American Heart Association. Accessed on February 24, 2009 at
  11. Lippuner K, et al. “Incidence and direct medical costs of hospitalisations due to osteoporotic fractures in switzerland.” Osteoporosis International.1997;7:414-25.
  12. WHO. Media Center. Fact sheet No. 297. February 2009 at

Source: Amgen Inc.


One step closer to personalized medicine

Stanford University Medical Center (2009, August 11). Professor Sequences His Entire Genome At Low Cost, With Small Team, ScienceDaily  –  The first few times that scientists mapped out all the DNA in a human being in 2001, each effort cost hundreds of millions of dollars and involved more than 250 people. Even last year, when the lowest reported cost was $250,000, genome sequencing still required almost 200 people. 

In a paper published online Aug. 9 by Nature Biotechnology, a Stanford University professor reports sequencing his entire genome for less than $50,000 and with a team of just two other people. 

In other words, a task that used to cost as much as a Boeing 747 airplane and required a team of people that would fill half the plane, now costs as much as a mid-priced luxury sedan and the personnel would fill only half of that car.

“This is the first demonstration that you don’t need a genome center to sequence a human genome,” said Stephen Quake, PhD, professor of bioengineering. “It’s really democratizing the fruits of the genome revolution and saying that anybody can play in this game.”

There are at least two reasons why lowering the cost and effort required to sequence all the genetic information of individuals is important. The more examples scientists have of the whole human genetic code, the more they can discern about how specific genes and mutations result in the traits that make us all different, the diseases that plague us and our response to medicines. As that understanding increases and costs drop, doctors could then sequence their patients’ genomes and provide “personalized medicine” in which prevention and treatment of disease would be informed by the patient’s exact genetic profile.

“This can now be done in one lab, with one machine, at a modest cost,” said Quake, the Lee Otterson Professor in the School of Engineering and a member of Stanford’s Cancer Center. “It’s going to unleash an enormous amount of creativity and really broaden the field.”

Quake’s genome, one of less than a dozen sequenced so far because of the cost and resources needed, is now available to researchers worldwide. Quake’s colleagues at Stanford’s School of Medicine have been looking through it and sometimes examining Quake himself, mining the data for interesting connections between what they can observe about him, his DNA and his family history.
“Some of the doctors are starting to poke and prod me to see how they can couple my genome with medicine,” he said.

Simpler sequencing

To sequence his genome, Quake’s team used a commercially available, refrigerator-sized instrument called the Helicos Biosciences SMS Heliscope. Quake, who pioneered the underlying technology in 2003, is a co-founder of the Cambridge, Mass.-based company and chairs its scientific advisory board.

The technology-the SMS in the instrument’s name-is called single molecule sequencing. While many techniques require generating thousands of copies of a subject’s DNA, the single molecule technique does not, reducing the cost and effort involved. Instead, the technique requires chopping the 3 billion or so fundamental units of DNA (called bases) into strands about 30 bases long. The four bases in DNA are adenine (abbreviated A), cytosine (C), guanine (G), and thymine (T).

Each base of DNA matches with a specific other base: For example, T only matches with A. The machine captures each of the millions of strands on a specially treated glass plate, holds them there and washes successive waves of fluorescently labeled “letters” over the plate. As each complementary letter sticks next to a strand, the machine can read out the sequence of each strand. A video of the process can be seen on the Web:

Assembling the strands back into a cohesive genome is then done by powerful computers, which compare it to the reference genomes that have been compiled before. The process is akin to assembling an enormous jigsaw puzzle by referring frequently to the picture on the box. The team said the sequencing process took about one month to complete.

Still, several tricky problems had to be solved before the machine could reliably sequence a whole human genome. Quake worked with Norma Neff, a research manager in Quake’s lab, and physics doctoral student Dmitry Pushkarev to write a sophisticated algorithm that would enable them to determine how accurate the process is.

Overall, the genome is 95 percent complete, a rate comparable with other sequenced genomes, the team found. In the paper, the authors are careful to note that all genome-sequencing technologies, including the one they’ve demonstrated, have produced incomplete approximations of the actual genome. Still, it is enough to help produce genuine insights about a person’s traits and health.

A professor’s personal revelations

Quake’s genome has already yielded a few interesting connections between his genetics and his health. One is that he carries a rare mutation associated with a heart disorder; the revelation, he said, sheds light on what members of his family have always wondered with regard to the health of prior generations. The good news, he said, is that he’s also apparently genetically predisposed to respond well to common cholesterol-lowering statin medicines.

Quake said the information has also forced him to take heed of that history. “If you know your uncle had something, you kind of discount that you can get it, but to see you’ve inherited the mutation for that is another matter altogether,” he said.

One amusing “revelation” is that Quake’s code contains a form of a gene that has sometimes been associated with increased disagreeability, he said. The details of the code can be found on the Web at

“Of course, you don’t need my genome to tell you that,” Quake acknowledged. “My wife could have told you that and certainly the dean could have as well.”

Funding for the research came from the National Science Foundation and from the National Institutes of Health.


Adapted from materials provided by Stanford University Medical Center. Original article written by David Orenstein, associate communications director, School of Engineering.


True Single Molecule Sequencing

By directly sequencing single molecules of DNA or RNA, Helicos’ True Single Molecule Sequencing(tSMS)TM technology significantly increases the speed of sequencing, while also decreasing the cost.

tSMS enables the simultaneous sequencing of large numbers of strands of single DNA or RNA molecules by using a proprietary form of sequencing-by-synthesis in which labeled DNA bases are sequentially added to the nucleic acid templates captured on a flow cell.  Our optimized formulation ensures high accuracy of each base addition, which are detected by the HeliScopeTM Single Molecule Sequencer to elucidate the sequence of bound strands.

Download the Helicos tSMS Technology Primer (pdf). 

How tSMS Works

Within two flow cells, billions of single molecules of sample DNA are captured on an application-specific proprietary surface. These captured strands serve as templates for the sequencing-by-synthesis process:

Polymerase and one fluorescently labeled nucleotide (C, G, A or T) are added.

  • The polymerase catalyzes the sequence-specific incorporation of fluorescent nucleotides into nascent complementary strands on all the templates.
  • After a wash step, which removes all free nucleotides, the incorporated nucleotides are imaged and their positions recorded.
  • The fluorescent group is removed in a highly efficient cleavage process, leaving behind the incorporated nucleotide.
  • The process continues through each of the other three bases.
  • Multiple four-base cycles result in complementary strands greater than 25 bases in length synthesized on billions of templates-providing a greater than 25-base read from each of those individual templates.


Raw tSMS Image


An image taken by the HeliScope Single Molecule Sequencer.
Inset shows a close-up view of individual single molecules.

Watch the Video
“How True Single Molecule Sequencing Works”

The Data Pipeline

The data pipeline of the HeliScopeTM Single Molecule Sequencer is designed for openness and flexibility. Data is available for export at several points during the production process.

Images, the object table, and sequence, trace and quality data are output in non-proprietary formats, either through the HeliScope Web Interface or HeliScope Application Programming Interfaces (APIs). We also use the HeliScope APIs in our internal development, ensuring quality of performance and timely maintenance.


Image Analysis

Using the latest in high-performance-computing technology and state of the art optics, the system’s image analysis software, located on the HeliScopeTM Analysis Engine, identifies and extracts millions of nucleotide base incorporations from the 48 images produced by the HeliScopeTM Single Molecule Sequencer each second – in near real time.

Features are identified according to stringent nucleotide incorporation criteria and catalogued in an “object table” for subsequent base calling and sequence formation.


True Biology


Direct Measurement: The Pathway to True Biology
Limitations in the detection sensitivity of traditional biological analysis tools, have often forced scientists to measure the properties of molecular aggregates and assume that these properties represent a true characterization of the constituent individual molecules. An example is high-throughput nucleic acid sequencing. Many current sequencing approaches depend on an amplification step to copy DNA and RNA before the base sequence is determined. Sequencing the copies of the sample, rather than the sample itself can mask the biology of the actual sample by introducing biases and errors.
Measure the biology of the cell; not the biology of the test tube
The essence of true biology is the ability to interrogate individual molecules of a sample directly, without depending on proxies. Helicos True Single Molecule Sequencing (tSMS)TM technology captures exactly that ability – to sequence and detect individual nucleic acid molecules without relying on an amplification process. With single molecule sequencing technology, the Helicos genetic analysis tools are poised to usher in a new era of high-fidelity, high-throughput genomic exploration.

True Direct DNA measurement enables high-resolution science

  • Accurate – The ability to optically detect individual nucleic acid incorporation events on a single strand of DNA or RNA allows unparalleled sequence accuracy.
  • Simple – Sample preparation is minimal, and does not require an amplification process. Instrument interface is intuitive and instrument operation is automated.
  • Unbiased – PCR-based DNA amplification can lead to biases because certain fragments reproduce at different rates, leading to the systematic overrepresentation of some segments and an underrepresentation of others. Helicos tSMS technology allows amplification-free sample prep.
  • Scalable – The density allowed by single molecule sequencing along with the flow cell design allows excellent scalability of samples and target size.
  • Sensitive – Single molecule detection and minimally altered samples allows unprecedented looks at rare mutations and transcripts expressed at low levels.

Helicos Translates Single Molecule Sequencing Into Real Research Power

  • Greater quantitative power to obtain true counts, rather than ratiometric data
  • Application flexibility for Digital Gene Expression, Targeted Resequencing, Copy-Number Variation Assessment, Chromatin Immunoprecipitation-Sequencing and others
  • Enhanced ability to discern rare mutations in heterogeneous samples and measure rare transcripts
  • Demonstrated freedom from amplification and fragment-length bias as well as from sequence context effects
  • Generation of more data through single molecule template density and flow cell design

Scalability and Simplicity

Bringing Together Power and Practicality
The door to true biology has been opened by the ability of the HelicosTM Genetic Analysis System to directly sequence and image individual molecules. The power of the single molecule approach can only be fully realized by integrating onto a robust and versatile instrument design and combining it with easy sample preparation. Helicos recognizes this, and has coupled the power of single molecule sequencing with the practicality of a flexible, easy-to-use instrument and simple sample preparation.  Detection at the single molecule level is only the beginning!

Scalability by design
Powered by Helicos tSMSTM technology, the system generates more data per run of any available sequencing technique, providing unmatched scalability. Superior data output is a result of the high density of sequenced DNA strands on the flow cell surface, as well as the 25-channel flow cell design (50 channels total). Generating this amount of data per run translates into a wealth of experimental flexibility, and into increased experimental validity.

Whether you have only tiny amounts of precious or degraded samples, or a large, genome-scale sample, the Helicos Genetic Analysis System offers:

  • Breadth of coverage-Run up to 50 samples simultaneously for deep coverage across a wide area or the whole genome, including both AT-rich and CG-rich regions
  • Depth of coverage-Run one sample on multiple channels simultaneously for deep coverage of a specific region
  • Elimination of variation-Increase data reliability and validity by avoiding run-to-run variation, operator-to-operator variation and reagent, sample loading or hybridization variability

The scalability enabled by the technology coupled with the accuracy of single molecule sequencing means experiments with high sensitivity.

Simplicity Start to Finish:
Helicos is dedicated to enabling your success.  So we combine the ability to conduct a range of different experiments on a single platform with the simplest sample preparation.

  1. Fewer steps saves time and money-fragment DNA, tail and hybridize to surface
  2. No amplification-single molecule sequencing does not require additional amplification

Intuitive instrument operation-the instrument has an easy-to-use touch screen interface and has fully automated reagent delivery and imaging capability

← Previous PageNext Page →