FDA Draft Guidance on:

Electronic Source Data in Clinical Investigations

 

Congratulations to FDA for the draft guidance on Electronic Source Data For Use in Clinical Investigations. This well-written guidance document clearly addresses the approaches needed for transitioning from the paper case report form (CRF) to the electronic world of the eCRF. This guidance is intended to be used together with the FDA guidance for industry on Computerized Systems Used in Clinical Investigations.

 

In an effort to streamline and modernize clinical investigations, the FDA has provided recommendations to sponsors, Contract Research Organizations (CROs), data management centers, clinical investigators, and others involved in capturing, reviewing, and archiving electronic source data in FDA-regulated clinical investigations. The guidance promotes capturing source data in electronic form, and it is intended to assist in ensuring the reliability, quality, integrity, and traceability of electronic source data. The guidance also addresses source data from clinical investigations used to fill the predefined fields in an electronic case report form (eCRF), according to the protocol. The guidance discusses the following topics related to electronic source data:

 

1. Identifying and specifying authorized source data originator

2. Creating data element identifiers to facilitate examination of the data audit trail

3. Capturing source data into the eCRF using either manual or electronic capture methods

4. Investigator responsibilities with respect to reviewing and retaining electronic data

 

As always, we will have some comments which will be posted on the FDA website no later than January 19, 2013. However, on first review, the document says it all. Footnote 3 on page 2 is very helpful to clarify the point that: “Investigators are required to maintain adequate and accurate case histories that record all observations and other data pertinent to an investigation under 21 CFR 312.62(b) and 21 CFR 812.140(a).”

 

From the Target Health perspective, the draft guidance document is fully consistent with our approach to the “paperless” clinical trial. Target e*CTR® (Target eClinical Trial Record, the electronic health record for clinical trials), will be the eSource records used for the first NDA submission to use a “paperless” approach for clinical data, and the 2nd NDA submission (1st one approved in 2012) to use Target Document® to manage the electronic Trial Master File (eTMF) for regulatory documents.

 

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

Fleming, Penicillin, Pfizer and WW2

 

A magazine ad for penicillin during WWII

 

 

The Scottish bacteriologist Sir Alexander 1) ___, (1881-1955), discovered penicillin. In 1906, Fleming (not related to Ian Fleming) received his medical degree from St. Mary’s Hospital in London. During World War I he began experimenting with antibacterial substances and in 1921 discovered lysozyme, an antibiotic enzyme that attacks many types of 2) ___. In 1928, when Fleming discovered the germ-killing properties of the “mold juice” secreted by Penicillium notatum, he knew that it could have profound 3) ___ value. But Fleming could not make enough penicillin to be useful in practice, and his discovery was dismissed as no more than a laboratory curiosity. Ten years later, a team of scientists at Oxford University rediscovered Fleming’s work. Armed with increasing evidence of the remarkable powers of penicillin, but unable to engage British companies due to the country’s involvement in World War II, the Oxford scientists sought help in 4) ___.

 

In 1941 John Davenport and Gordon Cragwall, representing the pharmaceutical company Pfizer, attended a symposium. At the symposium researchers from Columbia University presented clear evidence that penicillin could effectively treat infections. Inspired by the possibilities, the two men offered Pfizer’s assistance. That same year, Pfizer was among the companies responding to a government appeal to join a high-stakes race to see which company would develop a way to mass-produce the world’s first “wonder 5) ___.” Beginning with fermentation experiments conducted with the team at Columbia University, Pfizer would take many risks over the next three years in devoting its energies to penicillin production. The substance was highly unstable, and initial yields were discouragingly low. But Pfizer was determined to succeed in the quest to mass-produce this lifesaving new drug.

 

In the fall of 1942, Pfizer scientist Jasper Kane suggested a completely different approach, proposing that the company attempt to produce penicillin using the same deep-tank fermentation methods perfected with citric acid. This was tremendously risky because it would require Pfizer to curtail the production of other well-established products while it focused on the development of penicillin. It could also place the company’s existing fermentation facilities in danger of becoming contaminated by the mobile penicillium spores. In a small room in the Brooklyn plant, Pfizer’s senior management team met to weigh the options and took the leap. The team voted to invest millions of dollars, putting their own assets as Pfizer 6) ___ at stake, to buy the equipment and facilities needed for deep-tank fermentation. Pfizer purchased a nearby vacant ice plant, and employees worked around the clock to convert it and perfect the complex production process. The plant was up and running in four months, and soon Pfizer was producing five times more penicillin than originally anticipated.

 

Penicillin, was, and is, one of the most active and safe antibacterial available. Because of their effectiveness and large therapeutic index, penicillin and many closely related derivatives, collectively known as the PENICILLINS, and the closely related 7) ___ (discovered in the 1960s) are among the most important families of antibacterial available today. Fleming shared the 1945 8) ___ Prize for physiology or medicine with the British scientist Ernst Boris Chain and Australian Howard Walter Florey, who were able to purify and obtain enough penicillin for human trials.

 

Recognizing the potential of the 9) ___ process for producing penicillin and desperate for massive quantities to aid in the war effort, the U.S. government authorized 19 companies to produce the antibiotic using Pfizer’s deep-tank fermentation techniques, which Pfizer had agreed to share with its competitors. Many of these companies could not come close to Pfizer’s production levels and quality. Ultimately Pfizer produced 10) ___ percent of the penicillin that went ashore with Allied forces at Normandy on D-Day in 1944 and more than half of all the penicillin used by the Allies for the rest of the war, helping to save countless lives.

 

WW2 medic’s penicillin kit

 

 

ANSWERS: 1) Fleming; 2) bacteria; 3) medical; 4) America; 5) drug; 6) stockholders; 7) Cephalosporins; 8) Nobel; 9) Pfizer; 10) 90

Looking back at WW2:

 

Winston Churchill (1874-1965)

 

 

Winston Churchill, September 4, 1939

 

 

Overcoming Handicaps is the Stuff of Greatness

 

Winston Churchill has remained one of the most admired leaders in modern history. He loudly and passionately warned the world about Hitler’s Germany long before the Fuehrer aroused other leaders’ suspicions. He was one of the few voices that warned of the rise of Hitler and a newly ascendant Germany. No one wanted to listen to the truth, but he persisted in speaking it anyway. He skillfully oversaw a teetering war effort and inspired his country to stand up against seemingly insurmountable odds. Not only could Churchill write a masterful speech, he could deliver one with true power and feeling. He was a superior orator and gave some of the greatest speeches in history. His voice was full of confidence and steadfastness. Many historians believe that Churchill was a genius who saved Great Britain and Europe.

 

Aristotle was the first to point out the link between madness and genius, including not just poets and artists but also political leaders.

 

During his severely depressed years in the political wilderness, Churchill saw the Nazi menace long before others did. His exhortations to increase military spending were rejected by Prime Minister Baldwin and his second-in-command, Chamberlain. When Chamberlain returned from signing the Munich agreement with Hitler in 1938, only Churchill and a small coterie refused to stand and cheer in parliament, eliciting boos and hisses from other honorable members.

 

At dinner that night, Churchill brooded: How could men of such honor do such a dishonorable thing? The depressive leader saw the events of his day with a clarity and realism lacking in others. Studies have shown that depression correlates with high degrees of empathy, a greater concern for how others think and feel. In one study, severely depressed patients had much higher scores on the standard measures of empathy than did a control group of college students; the more depressed they were, the higher their empathy scores. This was the case even when patients were not currently depressed but had experienced depression in the past.

 

Churchill experienced recurrent severe depressive episodes, during many of which he was suicidal. Even into his later years, he would complain about his “black dog” and avoided ledges and railway platforms, for fear of an impulsive jump. “All it takes is an instant,” he said. “I don’t like standing near the edge of a platform when an express train is passing through. I like to stand right back and if possible get a pillar between me and the train. I don’t like to stand by the side of a ship and look down into the water. A second’s action would end everything. A few drops of desperation.”

 

Churchill’s depressive periods tended to be intense and prolonged. Sometimes they were connected with traumatic external events such as his dismissal from the Admiralty after the Dardanelles disaster in WWI. Other times they could not be attributed to such outside causes, fitting the classic profile of serious unipolar or bipolar depression. His depressions came and went throughout his long and remarkable life, and commenced in his youth. Churchill seemed to be aware that his depression was a medical condition. In 1911 a friend of Churchill’s claimed to have been cured of depression by a doctor. Churchill wrote about this with some excitement in a letter to his wife, Clementine: “I think this man might be useful to me – if my black dog returns. He seems quite away from me now – it is such a relief. All the colors come back into the picture.”

 

Today we can only make a retrospective diagnosis linking Winston Churchill and bipolar disorder, if we have evidence of mood swings – not depression alone. According to Sir Winston’s close friend Lord Beaverbrook, the great man was always either “at the top of the wheel of confidence or at the bottom of an intense depression.” This does sound like a description of Winston Churchill and manic depression.

 

In Churchill’s own writings is a description of his depression. Tellingly, he remarks that many days he could not get out of bed for the depth of the depression. Research has demonstrated strong links between bipolar disorder and substance abuse. Studies show that bipolar people are much more likely than depressed people, or the population at large, to be alcoholic. Further, alcoholics are more likely than members of the general population to be bipolar. Do manic depressives self-medicate this way to gain relief from the irritability, agitation and restlessness of mania?

 

Churchill’s favorite drink was whisky and soda, starting soon after breakfast. He is on record as having once drunk 11 of these during a single meal. When Churchill traveled to the US during Prohibition, he obtained a doctor’s note to certify that regular consumption of alcoholic spirits was necessary to his health.

 

Churchill also suffered from hearing loss but, interestingly, was more secretive about his hearing loss than he was about his depression. Churchill made no mention of hearing loss in his own published works, nor is it discussed by his early biographers, except as an adjunct to his age. The first detailed mention of his hearing loss is found in the 1966 biography, “Churchill: Taken from the Diaries of Lord Moran,” written by Churchill’s personal physician, Sir Charles Wilson (Lord Moran). Lord Moran told an interesting story about the Potsdam Conference of 1945. During this conference, President Truman, Stalin, and Churchill discussed the occupation of post-war Germany, and issued an ultimatum to Japan. Churchill had not read the briefs. Stalin was better prepared and would put sharp questions to Churchill, who would turn to his team and say, “What is the answer to that?” One of his team said, “We had to hiss the answers which he could not hear, and the whole thing became a shambles as a result.”

 

In 1962, Churchill had a visit from Dr. Robert Davidson, President emeritus of Westminster College, and his colleague. Dr. Davidson said, “Mr. Churchill was in bed during the interview; he was recovering from a fall. As I entered the room, his aide told me to sit at the head of the bed on Churchill’s right. There was a microphone under the bedclothes at that side of the bed. My colleague sat on the other side.” “I found Mr. Churchill very lucid and we conversed on a variety of topics during the visit. However, my colleague commented after we left, ‘The old boy is completely senile I suspect. He didn’t respond to anything I said.’ Of course, this was because he was seated out of the range of the microphone. Mr. Churchill’s age and hearing impairment had most certainly not affected his mind!”

 

Dr Paul Gilbert, author of the best seller Overcoming Depression, thinks that depression is an automatic response that we share with other mammals and is one of the human defenses. It is safer for the animal which lost to a stronger member of its group, to tone down its behavior to prevent a prolonged and losing struggle. Abandoned offspring which “close down and don’t make too much noise,” said Dr Gilbert, are less vulnerable to predators. During a depressed state we ruminate on the problems we have or we believe we have. While this forced introspection is a painful experience it helps making better decisions.

 

Churchill suffered a mild stroke while on holiday in the south of France in the summer of 1949. In June 1953, when he was 78, Churchill suffered a more severe stroke at 10 Downing Street. News of this was kept from the public and from Parliament, who were told that Churchill was suffering from exhaustion. He went to his country home, Chartwell, to recuperate from the effects of the stroke which had affected his speech and ability to walk. He returned to public life in October to make a speech at a Conservative Party conference at Margate. However, aware that he was slowing down both physically and mentally, Churchill retired as prime minister in 1955 and was succeeded by Anthony Eden. He suffered another mild stroke in December 1956. In the 1959 General Election Churchill’s majority fell by more than a thousand, since many young voters in his constituency did not support an 85-year-old who could only enter the House of Commons in a wheelchair. As his mental and physical faculties decayed, he began to lose the battle he had fought for so long against the “black dog” of depression.

 

There was speculation that Churchill may have had Alzheimer’s disease in his last years, although others maintain that his reduced mental capacity was merely the result of a series of strokes. In 1963, US President John F. Kennedy, acting under authorization granted by an Act of Congress, proclaimed him an Honorary Citizen of the United States (the first and only such honor ever granted), but he was unable to attend the White House ceremony.

 

Despite poor health, Churchill still tried to remain active in public life. On 15 January 1965, Churchill suffered a severe stroke that left him gravely ill. He died at his London home nine days later, at age 90, on the morning of Sunday 24 January 1965, 70 years to the day after his father’s death.

 

Getty Images: Winston Churchill

 

 

Named the Greatest Briton of all time in a 2002 poll, Churchill is widely regarded as being among the most influential people in British history.

 

One of Churchill’s famous speeches is followed by an interesting Discovery Channel series called Altered Statesmen, which documents Churchill’s more personal, issues, not usually discussed:

 

  1. 1.      “Now, we are the masters of our fate”
  2. Churchill: Altered Statesmen # 1
  3. Churchill: Altered Statesmen # 2
  4. Churchill: Altered Statesmen # 3
  5. Churchill: Altered Statesmen # 4
  6. Churchill: Altered Statesmen # 5
  7. Churchill: Altered Statesmen # 6
  8. Churchill: Altered Statesmen # 7
  9. Churchill: Altered Statesmen # 8

 

 

Editor’s note: This short article which includes the subject of depression, wants readers to know, that in no way does our opinion flag, regarding the greatness of Winston Churchill, in fact, it grows with even greater enthusiasm.   With Churchill, there could be an isomorphic correspondence between his personal battles, and those existing on the world stage.  With his clarity of reality, vision of the future and genius to guide him, Winston Churchill succeeded in winning on both levels.  He was truly one of the great players in all of world history.

Research Breakthrough Selectively Represses the Immune System

 

 

Autoimmune disorders occur when T-cells – a type of white blood cell within the immune system – mistake the body’s own tissues for a foreign substance and attack them. Current treatment for autoimmune disorders involves the use of immunosuppressant drugs which tamp down the overall activity of the immune system. However, these medications leave patients susceptible to infections and increase their risk of cancer as the immune system’s normal ability to identify and destroy aberrant cells within the body is compromised.

 

According to an article published online in Nature Biotechnology (18 November 2012), a mouse model of multiple sclerosis (MS), has been developed, using innovative technology, to selectively inhibit the part of the immune system responsible for attacking myelin. Myelin is the insulating material that encases nerve fibers and facilitates electrical communication between brain cells.

 

The new research takes advantage of a natural safeguard employed by the body to prevent autoreactive T-cells — which recognize and have the potential to attack the body’s healthy tissues — from becoming active. One of these natural mechanisms involves the ongoing clearance of apoptotic, or dying, cells from the body. When a cell dies, it releases chemicals that attract specific cells of the immune system called macrophages. These macrophages gobble up the dying cell and deliver it to the spleen where it presents self-antigens — tiny portions of proteins from the dying cell — to a pool of T-cells. In order to prevent autoreactive T-cells from being activated, macrophages initiate the repression of any T-cells capable of binding to the self-antigens.

 

One of the authors was the first to demonstrate that by coupling a specific self-antigen such as myelin to apoptotic cells, one could tap into this natural mechanism to suppress T-cells that would normally attack the myelin. The lab spent decades demonstrating that they could generate antigen-specific immune suppression in various animal models of autoimmune diseases. Recently, a preliminary clinical trial was initiated to test the safety of injecting the antigen-bound apoptotic cells into patients with MS. While the trial successfully demonstrated that the injections were safe, it also highlighted a key problem with using cells as a vehicle for antigen delivery: that is cellular therapy is extremely expensive as it needs to be carried out in a large medical center that has the capability to isolate patient’s white blood cells under sterile conditions and to re-infuse those antigen-coupled cells back into the patients. This is a costly, difficult, and time-consuming procedure.”

 

After trying out various formulations, the desired antigens were successfully linked to microscopic, biodegradable particles which could be taken up by circulating macrophages similar to apoptotic cells. Much to the amazement of the investigators, the antigen-bound particles were just as good, if not better, at inducing T-cell tolerance in animal models of autoimmune disorders. Then, using their myelin-bound particles, the authors were able to both prevent the initiation of MS in their mouse model as well as inhibit its progression when injected immediately following the first sign of clinical symptoms.

 

The research team is now hoping to begin phase I clinical trials using this new technology. The material that makes up the particles has already been approved by the FDA and is currently used in resorbable sutures as well as in clinical trials to deliver anti-cancer agents. The authors believe that the proven safety record of these particles along with their ability to be easily produced using good manufacturing practices will make it easier to translate their discovery into clinical use.

Effect of Three Decades of Screening Mammography on Breast-Cancer Incidence

 

 

In order to reduce mortality, an effective screening procedure must detect life-threatening disease at an earlier, more curable stage. Effective cancer-screening programs therefore both increase the incidence of cancer detected at an early stage and decrease the incidence of cancer presenting at a late stage.

 

A study, published in the New England Journal of Medicine (2012;367:1998-2005) used Surveillance, Epidemiology, and End Results (SEER) data to examine trends from 1976 through 2008 in the incidence of early-stage breast cancer (ductal carcinoma in situ and localized disease) and late-stage breast cancer (regional and distant disease) among women 40 years of age or older.

 

Results showed that introduction of screening mammography in the US was associated with a doubling in the number of cases of early-stage breast cancer that are detected each year, from 112 to 234 cases per 100,000 women – an absolute increase of 122 cases per 100,000 women. Concomitantly, the rate at which women present with late-stage cancer has decreased by 8%, from 102 to 94 cases per 100,000 women – an absolute decrease of 8 cases per 100,000 women. With the assumption of a constant underlying disease burden, only 8 of the 122 additional early-stage cancers diagnosed were expected to progress to advanced disease. After excluding the transient excess incidence associated with hormone-replacement therapy and adjusting for trends in the incidence of breast cancer among women younger than 40 years of age, it was estimated that breast cancer was overdiagnosed (i.e., tumors were detected on screening that would never have led to clinical symptoms) in 1.3 million U.S. women in the past 30 years. In addition, it was estimated that in 2008, breast cancer was overdiagnosed in more than 70,000 women; this accounted for 31% of all breast cancers diagnosed.

 

According to the authors, despite substantial increases in the number of cases of early-stage breast cancer detected, screening mammography has only marginally reduced the rate at which women present with advanced cancer. The authors added that although it is not certain which women have been affected, the imbalance suggests that there is substantial overdiagnosis, accounting for nearly a third of all newly diagnosed breast cancers, and that screening is having, at best, only a small effect on the rate of death from breast cancer.

Save Your Money: Fish Oil and Postoperative Atrial Fibrillation

 

 

To save some of our hard-earned tax payers’ money, this is an ideal study to be performed as a point-of-care clinical trial using the electronic health record. After providing informed consent, give the drug order to the hospital pharmacy and get the outcome data at time of discharge directly from the EHR.

 

Postoperative atrial fibrillation or flutter (AF) is one of the most common complications of cardiac surgery and significantly increases morbidity and health care utilization. A few small trials have evaluated whether long-chain n-3-polyunsaturated fatty acids (PUFAs) reduce postoperative AF, with mixed results. As a result, a study reported in the Journal of the American Medical Association (2012;308:2001-2011), was performed to determine whether perioperative n-3-PUFA supplementation reduces postoperative AF.

 

The Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) double-blind, placebo-controlled, randomized clinical trial, included a total of 1,516 patients scheduled for cardiac surgery in 28 centers in the United States, Italy, and Argentina. Inclusion criteria were broad and the main exclusions were regular use of fish oil or absence of sinus rhythm at enrollment. Patients were randomized to receive fish oil (1-g capsules containing >840mg n-3-PUFAs as ethyl esters) or placebo, with preoperative loading of 10g over 3 to 5 days (or 8 g over 2 days) followed postoperatively by 2g/d until hospital discharge or postoperative day 10, whichever came first.

 

The main outcome measure was occurrence of postoperative AF lasting longer than 30 seconds. Secondary end points were postoperative AF lasting longer than 1 hour, resulting in symptoms, or treated with cardioversion; postoperative AF excluding atrial flutter; time to first postoperative AF; number of AF episodes per patient; hospital utilization; and major adverse cardiovascular events, 30-day mortality, bleeding, and other adverse events.

 

At enrollment, mean age was 64 years; 72.2% of patients were men, and 51.8% had planned valvular surgery. The primary end point occurred in 233 (30.7%) patients assigned to placebo and 227 (30.0%) assigned to n-3-PUFAs (P=0.74). None of the secondary end points were significantly different between the placebo and fish oil groups, including postoperative AF that was sustained, symptomatic, or treated (231 [30.5%] vs 224 [29.6%], P=0.70) or number of postoperative AF episodes per patient (1 episode: 156 [20.6%] vs 157 [20.7%]; 2 episodes: 59 [7.8%] vs 49 [6.5%]; >3 episodes: 18 [2.4%] vs 21 [2.8%]) (P = .73). Supplementation with n-3-PUFAs was generally well tolerated, with no evidence for increased risk of bleeding or serious adverse events.

 

According to the authors, this large multinational trial among patients undergoing cardiac surgery, perioperative supplementation with n-3-PUFAs, compared with placebo, did not reduce the risk of postoperative AF.

TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.

 

FDA Approves Pump for Heart Failure Patients Awaiting Heart Transplant

 

Heart failure occurs when the heart is unable to pump blood normally throughout the body. Factors that can lead to heart failure include high blood pressure, narrowing or blockages in the heart’s blood vessels, and heart infections. Heart failure is considered end-stage when the underlying condition remains severe and no longer responds to medical therapy or other treatment options. Those with end-stage heart failure may need a heart transplant to survive.

 

A left ventricular assist device (LVAD) is a mechanical pump used to support heart function and blood flow in people who have weakened hearts. LVADs are the most common type of ventricular assist devices, and they help the heart’s left ventricle pump oxygen-rich blood to the body. LVADs can be used as a “bridge” therapy for these patients until a suitable donor heart becomes available.

 

This is the first time the FDA has approved a LVAD using registry data as a control. The INTERMACS registry collects information on patients implanted with approved mechanical circulatory support devices (MCSDs). The INTERMACS registry was established in 2005 as a joint effort involving the FDA, National Heart, Lung and Blood Institute (NHLBI), Centers for Medicare and Medicaid Services (CMS), clinicians, scientists, and industry. INTERMACS is managed by the University of Alabama at Birmingham.

 

The FDA approved the HeartWare Ventricular Assist System LVAD to support heart function and blood flow in patients with end-stage heart failure who are awaiting a heart transplant. The HeartWare System includes an implantable pump with an external driver and power source. It is designed for use inside or outside the hospital.

 

Other available LVADs require components to be placed in the abdomen. The HeartWare System is small enough to be implanted in the chest near the heart, allowing for implantation in smaller adults or patients unable to have an implant in the abdomen. The life-saving benefits of the LVAD in the intended patient population outweigh the risks observed during the clinical trial.

 

The FDA approved the HeartWare LVAD based on data from a clinical trial known as the ADVANCE trial. The trial compared outcomes from 137 advanced heart failure participants using the HeartWare System with outcomes from similar patients followed by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS).

 

Survival outcomes were comparable in the HeartWare LVAD and INTERMACS groups. Key serious adverse events such as infection and stroke were assessed in the clinical trial and compared with adverse events discussed in the scientific literature based on clinical trials or postmarket studies of other LVADs. Although rates of most key adverse events were comparable, the risk of stroke associated with the HeartWare LVAD necessitates patients and clinicians to discuss all treatment options before deciding to use the device.

 

The HeartWare Ventricular Assist System is manufactured by HeartWare Inc. of Framingham, Mass.

Homage: Ian Flemming Recently Opened 2012 James Bond

 

The James Bond Martini Recipe

 

Casino Royale Martini, Ian Fleming, 1953: ‘Dry martini in large champagne glass, three measures of Booths, one of vodka, one measure of Kina Lillet… shake (don’t stir) … then add zest of lemon.’

 

 

The quote is up on the wall, prominently placed in an attractive leafy courtyard, as soon as you enter the Lillet distillery. Casino Royale, Ian Fleming, 1953: ‘Dry martini in large champagne glass, three measures of Booths, one of vodka, one measure of Kina Lillet – shake (don’t stir) – then add zest of lemon.’’

 

Lillet is still made at the original site, where the distillery and cellars have been located since 1872. Its smart red, white and blue building is in Podensac, a village of 3,000 inhabitants that is in the Graves region of Bordeaux, 30km south of the city and around ten minutes from the famous sweet wines of Sauternes. It’s not surprising then, that this classic Bordeaux aperitif is made from a base of dry wine, and that typically the wine is a blend of Sauvignon Blanc and Semillon, but with more emphasis on Semillon – the favored grape of Sauternes.

 

The drink was invented by two brothers, Paul and Raymond Lillet, who were distillers producing a range of fruit eaux-de-vies. In the 19th century, Bordeaux was the most important port city in France, and fruits and spices were coming in from all over the world, giving them access to a range of exotic fruits and spices to distill and turn into liqueurs. Five years after setting up the distillery, they came up with the recipe for an aperitif made from the plentiful local wines, mixed with the very fashionable quinine (tonic water had been granted an English patent in 1858, and quinine continued to be seen as a healthful tonic, and pretty much the only treatment against malaria and other fevers, until after World War II), plus a range of fruit liqueurs. As the 20th century got underway, they stopped making the other eaux-de-vie and concentrated just on Lillet Blanc.

 

 

The exact recipe remains secret. In all, the drink is 85% wine, and around 15% fruit liqueurs which include a base of sweet oranges from Valencia in Spain, green oranges from Morocco and Tunisia, bitter oranges from Haiti and cinchona bark (or quinine) from rainforests in the Peruvian Andes. Today they get the fruit peels sent in rather than the whole fruit (there was once jam production on site to use the excess fruit), but the cold soaking and maceration is done in their cellars, taking between three and six months.

 

The popularity of Lillet was at its height in the 1930s, when it sold around 180,000 bottles a year (it is back up to this number today), but after World War II, sales declined as France discovered whiskey and pastis. In the 1960s, the company began making red Lillet, from a base of local red wine. Lillet Rouge is more tannic than the white, more structured and is full of red fruits, almost like a good quality sangria. With this invention, and a resurgence of Lillet Blanc for cocktails in the US, sales began to rise again.

 

In 1985, Bruno Borie, owner of Chateau Ducru Beaucaillou, bought the business from the Lillet family (some of whom still remained working in the company. Pierre Lillet, the 93 year old grandson of the original owner, and previous cellar master himself, still comes by the offices every day to see how things are going, while other members of the family have long been among Bordeaux’s most important courtiers, or wine brokers).

 

The first thing Borie did was relook at the recipe of Lillet Blanc and make it fruitier, lighter, less sugary but also less bitter, as he reduced the levels of quinine – to achieve the balance of sweetness and sourness that it has today. A Reserve Jean de Lillet Blanc was also created, that more closely resembles the original recipe, tasting somewhere between a Sauternes and today’s Lillet aperitif. With the new recipe, he relaunched the drink. At the time, sales were 24,000 in France, but when he sold it in 2008 (to the Ricard family of Pernod-Ricard), sales had reached 400,000 in France, with another 400,000 overseas. When it featured in 2006 film version of Casino Royale, where Daniel Craig asking for a martini with Kina Lillet, sales particularly in the US shot up by 20%.

 

 

For both red and white, the Lillet team select their wines from across Bordeaux – Sauternes, Graves, the Cotes de Bordeaux, Entre deux Mers and others – through wine brokers, who find samples that match requirements and get those samples sent to Podensac. The ideal base white wine is rich and perfumed, and the red should be soft and round, but well structured, based on the merlot grape. The cellar master then tastes and chooses the best batches, and does the blending himself. Its production mirrors in many ways that of the region’s wine – put into cement tanks on arrival in the cellar, then blended and aged for one year in large oak vats. Before being put into the oak vats, the wine is blended with the 10 fruit-based liqueurs in an operation known here as ‘Le Vinage’.

 

Production is constant throughout the year, and is made of a blend of vintages, a bit like Champagne, to ensure the taste remains consistent from year to year. A little of the final blend from each batch is kept behind to form the base for the next one. The Reserve wine comes from just one estate, and just one vintage, and is aged in a mix of 400 litre and 225 litre oak barrels for one year (2/3 new, 1/3 one year).

 

The final drink needs to be served very cold, because that emphasizes the fruit aromas rather than the bitterness. As the drink warms, the bitterness becomes more obvious. You can add ice, but should also add a slice of lemon (orange for Red Lillet) so it doesn’t dilute the principal flavors as the ice melts. The finish is dry from the quinine, which is why it is still considered to be fortifying and reviving drink, perfect for stimulating the appetite as an aperitif.

 

www.lillet.com – Open for visits every day during July and August. Rest of year by appointment. Source: Lillet: the classic Bordelaise aperitif – (originally written for Flavors from France, May 2009)

 

Stormy Weather

 

By Mark L. Horn, MD, MPH, Chief Medical Officer, Target Health Inc.

 

The editors of On Target have been generous in affording me a regular platform to address readers. I have tried to return their favor by focusing on timely topics of broad interest upon which I can hopefully shed some light. In most instances these informal, admittedly self-imposed rules render personal experiences unsuitable for discussion.

 

This week, however, will be an exception. A personal experience has converged with a regional disruption and warrants mention.

 

The morning after Hurricane Sandy visited us in the ‘tri-state area’ my wife and I returned from the hotel where we had gone to spend the night in anticipation of the storm to find several large trees intimately engaged with what had been our roof. The house was obviously uninhabitable (a status soon officially confirmed by our Borough), and we instantly became itinerant homeless.

 

The ongoing saga has been transformative in many ways; among these are an enhanced sensitivity to the suffering of so many in our region who have been more severely hurt than we and an enormous gratitude and appreciation for the critical assistance offered by so many – assistance which, for the first time I can recall as an adult, we genuinely needed, and accepted. (For some inexplicable reason we never asked “Why us?”, although as we cope with the various insurance and contracting issues that question may well surface.)

 

More broadly, as a member of our local medical community, the apparently successful efforts to transfer and care for so many acutely ill, hospitalized patients requiring emergency evacuation from major medical centers suddenly deprived of the critical systems is a source of pride. Since many major institutions, including Bellevue Hospital and the Manhattan VA (both of which I recall with genuine affection from my medical school days) remain compromised, other institutions have stepped up in the emergency. At this writing stability seems to have been achieved in an admittedly strained system.

 

At a more personal level, I witnessed the commitment of many individual physician friends, often living in dark cold houses with no hot water, to quickly reopen their offices and maintain patient care. Virtually everyone complained about the discomfort, but their real focus was on offering care in a most difficult situation. Parenthetically, some of the comments about the inability to access electronic health records in this situation suggest some attention be paid to how to best back up these increasingly critical systems.

 

While in many ways the system worked, some questions warrant consideration. Among these, it seems there were multiple failures of emergency generators. The hotel where we stayed experienced a failure, and the wonderfully responsive and considerate staff told us that they’d called the repair service and gotten voice-mail. This is common, frustrating, irritating, but overall trivial generally, but it seems almost an oxymoron when an emergency system fails in a critical situation and one cannot access help. Similarly, even now there are reports of elderly people in apartments without elevator service who are having difficulty securing the basic necessities of life. This seems an entirely predictable occurrence after a major storm, preventable with proper planning.

 

So, while the overall report card is mixed, as best I can tell the health care folks, writ large, seem to have handled the emergency well.

 

On Target editors permitting, I shall keep the readers posted on our personal and regional progress, please keep us all in your thoughts.

and all the bloggers, wish everyone a

Happy Thanksgiving!

 

The Not-So-Hidden Calories From Alcohol

 

Dan Neville/The New York Times –  Are there too many calories hiding in your Thanksgiving toast?

 

 

The New York Times, November 20, 2012, by Anahad O’Connor  —   Hoping to stave off weight gain in the coming weeks? You may want to hold off on the mulled wine and cocktails this holiday season, according to a new report that looked at the number of calories Americans get from alcoholic beverages.

The study, which used nationwide data collected between 2007 to 2010, found that the average adult consumes about 100 calories worth of alcohol daily — an amount that for many people could contribute to excess weight gain. In fact, the study found, many Americans consume far more than 100 calories of alcohol a day: 20 percent of men and 6 percent of women drink more than 300 calories worth daily, roughly the amount in two 12-ounce cans of beer or two-and-a-half glasses of wine.

Of course, it is no secret that Americans get many of their calories in liquid form. The average person consumes between 140 and 180 calories worth of sugary drinks a day, which according to health officials is enough to pack on several pounds a year. Soda bans in school cafeterias and initiatives like Mayor Michael R. Bloomberg’s ban on the sale of large sodas and other sugary drinks in New York City have also highlighted concerns about the link between obesity and liquid calories. But until now researchers had never looked in detail at the calories Americans were getting from alcoholic drinks.

“Most of the research has focused on sugar sweetened beverages,” said Samara Joy Nielsen, the lead author of the study and a nutritional epidemiologist with the National Center for Health Statistics, part of the Centers for Disease Control and Prevention. “No one has ever really looked at alcohol from a caloric perspective.”

One reason for the new study, Dr. Nielsen said, was to quantify a source of calories that Americans rarely give much thought to.

“I think people may be aware that there are calories in alcoholic beverages,” she said, “but I don’t know if people actually look at a beer and realize that it’s the same amount of calories as a soda. Or that a five-ounce glass of wine is almost as much as a soda.”

To get a better sense of the number of calories alcohol contributes to the average American diet, Dr. Nielsen and her colleagues examined data from the long-running National Health and Nutrition Examination Survey, which provides some of the most reliable statistics available on Americans’ health. This was the first time that the group had examined the calories from alcoholic beverages. “Previously, the focus has been sugar sweetened beverages, including soda and fruit drinks,” she said.

The research, published on the C.D.C. Web site, involved more than 11,000 people across the country over the age of 20 who provided details on the foods and drinks they consumed in a typical day.

Dr. Nielsen and her team found that on a given day, one third of men and 18 percent of women have at least one alcoholic drink. All told, among those who drink, alcohol accounted on average for about 16 percent of their daily calories.

But the study also found that there were clear age and gender divides. Men, not surprisingly, typically drink more than women, having on average 150 calories worth of alcohol a day compared to a little over 50 calories for women.

Younger adults appeared to be heavier drinkers. Men between the ages of 20 and 39 consumed roughly 175 calories of alcohol a day, almost double the 96 calories worth of alcohol consumed by men over the age of 60. Women between the ages of 20 and 59 drank about 60 alcohol calories on average, while older women consumed about half that, roughly 33 alcohol calories a day.

Race and ethnicity seemed to have little influence on the amounts consumed. But income played a role: the highest earners also had the highest levels of imbibing. As for the types of alcohol that Americans turned to, there was little surprise when it came to men. Beer was a heavy favorite, especially among younger people. But the researchers found something they were not expecting when they looked at what women were drinking. Women were consuming equivalent numbers of calories from wine, liquor and beer.

“I think we confirmed what people think about men consuming more alcoholic beverage calories from beer,” said Dr. Nielsen. “But I find it interesting that women on average consume approximately equal numbers of calories from beer, wine and liquor.”

“This is a time of year where potentially people could be drinking more,” she added, “and I think sometimes people forget completely that alcoholic beverages have calories.”

 

Next Page →