Why an HIV Vax Only Works for Some

The only HIV vaccine to show promising efficacy in clinical trials stimulated an antibody-based defence in some individuals but not in others. Analysing patients’ samples from a large trial that took place in Thailand between 2003 and 2005, researchers have now identified a subgroup of study participants who express a human leukocyte antigen (HLA) allele linked to reduced risk of HIV infection after vaccination. The results of this latest analysis were published today (July 15) in Science Translational Medicine.

The highly mutable nature of HIV makes vaccine design particularly challenging. (See “Defeating the Virus,” The Scientist, May 2015.) Individual variation in immune response adds another layer of difficulty. The present study provides additional information on the range of possible immune responses to an HIV vaccine.

“Understanding why [the vaccine] appeared to work in some individuals and may not have worked in others is really paramount to moving the field closer to an effective [HIV] vaccine,” said Bruce Walker, director at the Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, who was not involved in the work. “We don’t yet know enough about how to turn vaccine non-responders into responders, but this is an important first step.”

Rasmi Thomas of the Walter Reed Army Institute of Research in Silver Spring, Maryland, led the international team—including investigators from Thailand’s Ministry of Public Health—that analyzed the HLA class II alleles and HIV antibodies present after immunization in 760 trial participants.

The US Army-sponsored RV144 trial randomized more than 16,000 people in Thailand at risk for HIV infection to either the vaccine or placebo. The efficacy rate, reported in 2009, was 31.2 percent, yet those who expressed the DPB1*13 HLA allele appeared to be better protected from HIV infection, according to this latest analysis. Individuals with the DPB1*13 variant who also had high levels of immunoglobulin G (IgG) antibodies against a portion of the HIV envelope had the lowest rate of HIV infection following immunization in the trial. The efficacy rate in this subgroup was 71 percent. In other words, those individuals who received the placebo were three times more likely to become infected with HIV compared to those immunized individuals who expressed the apparently protective HLA allele.

“We already knew vaccine recipients that showed a certain type of IgG antibody response against a region of the HIV envelope were less likely to become infected with HIV,” Thomas wrote in an e-mail to The Scientist. “We now see that not everyone who produced this good type of antibody response was protected, but only those who had the DPB1*13 HLA variant.”

Specifically, higher levels of IgG antibodies against a 25 amino acid N-terminus portion of the HIV gp120 protein—encoded by the Env gene—conferred more effective immunity in those with the DPB1*13 allele. This portion of the highly variable protein, part of the virus’s outer envelope, is relatively conserved among the most common substrains of HIV.

A previous analysis of trial participants identified anti-Env IgA antibodies associated with reduced vaccine efficacy. This latest analysis further refined this non-responder subgroup, pinpointing individuals who not only generated these IgA antibodies but also expressed the DQB1*06 HLA allele.

Not everyone is so sure that lessons learned from the RV144 trial will advance HIV vaccine strategies. John Moore, who studies HIV-1 Env proteins at Weill Cornell Medical College in New York City is “not convinced that this kind of analysis helps in Env vaccine design.” Moore toldThe Scientist in an e-mail that he questions how antibodies of interest to the RV144 researchers might interact with Env to impede infection.

Walker, too, noted that immune responses may be specific to this vaccine. “This is one of the frustrations in the field,” he said. “We really don’t know if the correlates of risk for one vaccine are the same for another vaccine.”

But Thomas remains optimistic. “The task now is to work out what was different about the protective antibody response, in specifically people with DPB1*13, that could have caused the protection from HIV,” she said. “If this difference could be identified, it may be possible to design a vaccine that could induce an effective response in all individuals.”

Lessons on HIV vaccine efficacy based on genetic differences among individuals may also be extended to vaccine design for other diseases including dengue fever, malaria, and Ebola, added Thomas.

Read More

Clinical Research Word Puzzle

Find 40 words used commonly in clinical research!

Read More

NCI’s Clinical Trials Programs and Initiatives

• Why Clinical Trials Are Critical to Progress against Cancer
• How New Knowledge about Cancer Is Changing Clinical Trials
• How NCI Programs Make a Difference
• Early-Phase Clinical Trials: Building on Basic and Preclinical Advances
• Phase II and Phase III Trials: Testing Effectiveness
• Correlative and Quality of Life Studies: Improving Standard Clinical Practice
• How NCI Is Supporting Cutting-Edge Clinical Trials

WHY CLINICAL TRIALS ARE CRITICAL TO PROGRESS AGAINST CANCER

Clinical trials are essential for moving new methods of preventing, diagnosing, and treating cancer from the laboratory to physicians’ offices and other clinical settings.In clinical trials, researchers carefully and methodically test drugs, medical devices, screening approaches, behavioral modifications, and other interventions. Trials are used to answer many different clinical questions relevant to all aspects of health care, such as whether a treatment can prevent cancer in people at increased risk, whether a new drug can extend the lives of patients with advanced cancer, or whether specific treatment approaches can improve patients’ quality of life. The Food and Drug Administration (FDA) typically requires proof of safety and effectiveness of a new anticancer drug in a large clinical trial before it can be used broadly in patient care.

In addition to testing new interventions, clinical trials can help determine the best use of existing interventions, test new approaches for increasing the number of people who seek follow-up care after a positive cancer screening test, and test ways to improve end-of-life care for patients.

Read More

Clinical trail Broadcast series……. part I

  1-The Power of Clinical Partnerships Zaher El-Assi, President of Merge eClinical, shares lessons learned and the core practices his company uses to forge long-term partnerships that produce value for both companies that goes beyond the traditional buy-sell relationship.
 

   

 2-How Information Technology is Leveling the Clinical Research Playing Field Zaher El-Assi, President of Merge eClinical, discusses the development and application of current and emerging technologies in clinical research. Advances in information technology are revolutionizing how CROs, sponsors and academic institutions can design and manage clinical studies. The growth of affordable, secure cloud-based software services, mobile communications and the digitization of clinical data is helping researchers worldwide conduct studies more quickly, efficiently and cost-effectively. In short, the impact of an organization’s size, budget or existing technology infrastructure on its ability to conduct or compete for trials is decreasing. This trend will accelerate in the next few years, offering a range of benefits for sites, sponsors and CROs as well as patients and medical professionals. Using the eClinicalOS platform from Merge eClinical as a case study, this podcast explores the development and application of current and emerging technologies in clinical research.

   

 3- Challenges with Oncology Trials in Ontario Karen Arts, is the Director of Business Development, High Impact Clinical Trials Program at the Ontario Institute for Cancer Research in Toronto, Canada discusses challenges in oncology trials in Ontario with Roberto Lara, Director of Business Development for Scimega Research.

Read More

Tramadol: Drug Safety Communication – FDA Evaluating Risks of Using in Children Aged 17 and Younger

ISSUE:  FDA is investigating the use of the tramadol in children aged 17 years and younger, because of the rare but serious risk of slowed or difficult breathing. This risk may be increased in children treated with tramadol for pain after surgery to remove their tonsils and/or adenoids. FDA is evaluating all available information and will communicate final conclusions and recommendations to the public when the review is complete.

Tramadol is not FDA-approved for use in children; however, data show it is being used “off-label” in the pediatric population. professionals should be aware of this and consider prescribing alternative FDA-approved for children.

BACKGROUND: In the body, tramadol is converted in the liver to the active form of the opioid, called O-desmethyltramadol. Some people have genetic variations that cause tramadol to be converted to the active form of the opioid faster and more completely than usual. These people, called ultra-rapid metabolizers, are more likely to have higher-than-normal amounts of the active form of the opioid in their blood after taking tramadol, which can result in breathing difficulty that may lead to death. Recently, a 5-year-old child in France experienced severely slowed and difficult breathing requiring emergency intervention and hospitalization after taking a single prescribed dose of tramadol oral solution for pain relief  following surgery to remove his tonsils and adenoids. The child was later found to be an ultra-rapid metabolizer and had high levels of O-desmethyltramadol in his body.

RECOMMENDATION: Parents  and caregivers of children taking tramadol who notice any signs of slow or shallow breathing, difficult or noisy breathing, confusion, or unusual sleepiness should stop tramadol and seek medical attention immediately by taking their child to the emergency room or calling 911. Parents and caregivers should talk with their child’s health care professional if they have any questions or concerns about tramadol or other pain medicines their child is taking.Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program:

---

• Complete and submit the report Online: www.fda.gov/MedWatch/report
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

[09/21/2015 – Drug Safety Communication – FDA]

Read More

Moving Beyond Price-Per-Dose In The Pharmaceutical Industry..

By Dana Goldman and Darius Lakdawalla

The United States has experienced extraordinary gains in treating cardiovascular disease over the last few decades. Statins, introduced in the 1980’s, are an important part of the story. Hundreds of thousands of deaths, heart attacks, and strokes have been prevented due to lower cholesterol, and the health benefits—appropriately valued—exceed $1.2 trillion. Evidence suggests there are around 40,000 fewer deaths and 60,000 fewer heart attacks annually because of these drugs. With sales that peaked around $30 billion annually, this makes statins—many of which are now generic—a very good deal.

A new generation of lipid-lowering therapies, PCSK9-inhibitors, will soon reach the market and could further extend these gains. These drugs significantly lower bad cholesterol levels (LDL) in the blood. For those who have exhausted other treatment options, PCSK9-inhibitors may reduce cardiovascular events by as much as 50 percent. However, given their announced prices, some payers are nervous about their use. And, given the benefits of statins, some might ask why PCSK9-inhibitors (PCSK9i) are needed.

Surprisingly, almost one-third of high-risk statin users are not reaching recommended lipid-lowering goals. Thus, while we have come a long way, many patients are still missing out on the benefits of lipid-lowering therapies.

The problem here is our creaky model of pharmaceutical pricing, which now threatens to deprive patients of these and other breakthroughs to come. For decades, the vast majority of drug manufacturers and payers have relied on pricing per dose, be it a pill, a milligram, or the like. While simple and convenient, the “price-per-dose” (PPD) model produces a number of well-known side effects that are now becoming increasingly severe.

PPD Limits Access To Novel Drugs

Setting a single unit price for a drug may be straightforward when it produces reliable and known clinical benefits in patients — in other words, when its mechanism of action has been observed for years in trials and real-world settings. The clinical benefits of novel drugs, however, remain inherently more uncertain.

Payers often respond to this uncertainty by delaying access to novel agents until convincing evidence arrives — sometimes years after product launch. In the case of PCSK9i, payers already seem poised to delay widespread access until clear and definitive evidence of cardiovascular event risk-reduction arrives. Unfortunately, this is likely to take another 2-4 years, which could mean thousands of adverse cardiovascular events in the meantime.

PPD Drives Up Prices For Patients That Derive Moderate Clinical Benefit

When manufacturers must set a single price for each dose, they predictably focus on patients with the very most to gain. This may sound appealing, but in many cases, the clinical benefits of new drugs vary across patient groups. Large numbers of patients stand to gain moderate amounts from a new drug, and added up over an entire population, these gains can be substantial.

With PCSK9-inhibitors, few doubt that patients with familial hypercholesterolemia whose LDL exceeds 500 mg/dL will get the new drugs. However, what about other high-risk patients whose LDL continues to exceed the recommended threshold of 70 mg/dL? The value created for these patients almost surely outweighs the cost of manufacturing the drugs. Failure to provide access thus represents a wasteful and inefficient outcome.

PPD Distorts The Dosing Decisions Of Physicians And Patients

Buying two bunches of bananas naturally costs twice as much as one bunch. Twice as many bananas can feed twice as many people. However, why should a patient who responds best to a 100 mg injection pay twice as much as another who happens to need a 50 mg version?

The 100 mg patient rarely receives twice as much value as her 50 mg peer. Even worse, charging more to patients on higher doses discourages physicians from titrating dosage upward, even when it is clinically warranted. What’s more, PPD forces us into a copayment model where patients are penalized for better adherence.

The Solution Is To Tie Reimbursement To Value

So what is the answer? We need to sever the link between price and doses for everyone, including patients. The best solution may be to reimburse pharmaceutical companies for PCSK9i therapies on the basis of heart disease risk—something cardiologists are already good at classifying—and to eliminate copayments per prescription regardless of patient risk. The highest risk group includes those with genetic disorders that elevate their cholesterol to dangerous levels, and who develop heart disease at a very early age. For these patients, the currently announced price of about $13,000/annually is a great deal.

But the answer is not to restrict the drugs just to this group. For other high-risk patients with less elevated cholesterol—e.g., atherosclerotic cardiovascular disease patients for whom statins lower LDL significantly, but not all the way to goal—a different, lower price should apply. With this differential pricing, payers would no longer have incentives to limit coverage. And, prescribing decisions would focus on the clinically optimal way to lower LDL, instead of on the least expensive dosing strategy.

Plans should pay manufacturers relatively more when the patient’s diagnosis warrants it, and less when the evidence base does not support such a price. This will also mean higher patient cost-sharing in the latter case.

We Need To Remove Barriers To Novel Pricing

Such economic arrangements face many obstacles, in spite of the obvious benefits. The first challenge is regulatory: how will such pricing arrangements be viewed by Medicaid?

Medicaid best-price rules make drug manufacturers reluctant to offer pricing schedules that could, in theory, result in very low unit prices for some groups of patients. The appearance of low unit prices in one or two market segments could theoretically drive down the prices paid by all state Medicaid agencies. As a result of this risk, Medicaid best-price rules have transformed the private insurance market in the US into one of the world’s least innovative testing grounds for new pricing strategies, even compared to public-sector payers overseas.

The second challenge concerns outcomes measurement. Who will assess the LDL reduction, or cardiovascular event-reduction, and how will it be measured? This problem, and its solution, is more common than it appears — for instance, acquisitions and mergers often depend on measuring financial performance. The typical solution is the use of a third-party auditor to verify measurement claims by, in this case, the payer. If we can develop protocols to monitor nuclear facilities in places like Iran, we can probably figure this one out.

Progress in biology and science has outstripped our economic institutions. Innovation in the pricing and reimbursement of pharmaceutical therapy is long overdue. Many challenges remain, but denying patients access to efficacious products is not the “safe” solution. The real risk lies in continuing business as usual, while patients bear the costs of delays and denials. If we price it right, perhaps we can make the next few decades as productive as the last few.

Read More

The Most Commonly Prescribed Drugs in America

by Napala Pratini

We remain a prescription nation. Nearly 70 percent of Americans take one prescription drug and more than half take two, according to researchers at the Mayo Clinic and Olmsted Medical Center. What’s more, about 20 percent of Americans use at least five prescription medications. That same research shows that prescription drug use has been increasing steadily in the U.S. for the past decade. With such a vast swath of the population relying on prescriptions, what drugs are being prescribed and why?

The most recent data available, an April 2014 study by the IMS Institute for Healthcare Informatics, a company that tracks sales at the pharmacy level for drug companies, shows that the top five medicines prescribed in the U.S. in 2013 were:

1. Hydrocodone/acetaminophen

2. Levothyroxine sodium

3. Lisinopril

4. Metoprolol

5. Simvastatin

These drugs are being prescribed in the millions, according to the IMS Institute. The numbers of prescriptions for each range from a high of 129 million for hydrocodone/acetaminophen, 115 million for levothyroxine sodium, 102 million for lisinopril, 84 million for metoprolol , and 79 million for simvastatin,

Uses for the most commonly prescribed drugs

The top drugs are used to treat a variety of ailments — from pain to high blood pressure and high cholesterol. Here’s a breakdown of the use of each drug:

Hydrocodone/acetaminophen is the nation’s most popular painkiller used to treat moderate to severe pain. Hydrocodone, a narcotic analgesic, relieves pain through the central nervous system, and it also is used to stop or prevent coughing. This drug’s reputation precedes it, as it can become habit-forming when used over an extended period of time.

Levothyroxine sodium is used to treat hypothyroidism, a condition where the thyroid gland doesn’t produce enough of the thyroid hormone. This drug also is used to treat thyroid cancer and to help shrink an enlarged thyroid gland.

Lisinopril (which used to be sold under the brand names Zestril and Prinivil) is a high blood pressure medication. Its main function is to block chemicals in the body that trigger the tightening of blood vessels. Lisinopril also is used to help treat heart failure.

Metoprolol is the generic version of Lopressor, is used to treat high blood pressure, and also helps reduce the risk of repeated heart attacks. Metoprolol also treats heart failure and heart pain, or angina.

Simvastatin (generic Zocor) is prescribed to treat high cholesterol and is typically recommended in conjunction with diet changes. This drug is believed to have a variety of benefits including helping to prevent heart attacks and strokes.

Cost of the drugs

The cost of each of these drugs is a slippery subject as the price varies depending on where you buy them and on your insurance coverage. Factors that influence cost include such things as how many tablets are in a prescription or how many milligrams are in each tablet. If you are prescribed a brand name drug, be sure to ask if there is a generic, since brand names tend to be 80-85% more expensive than generics, which legally cannot differ in efficacy, potency, quality or safety.

Here are some cash price estimates for the five drugs at CVS based on GoodRx searches in San Francisco. Keep in mind that your costs will differ based on your insurance status and drug co-pays associated with your plan.

Hydrocodone/acetaminophen: $47

Levothyroxine sodium: $12

Lisinopril: $14

Metoprolol: $17

Simvastatin: $38

Discount programs

There are a variety of ways to save money on prescription drugs. If you’re paying cash for your prescription medications, look into drug coupons — from a website like GoodRx — or in weekly discount fliers and direct mailings from major pharmacies.

Another way to save money on prescriptions is to shop through an online pharmacy, which can shave 35% or more off the cost of your medication. If you go this route, your doctor can fax or mail the prescription to the online pharmacy, then the medicine is mailed to you.

Some states, such as Washington and Kentucky, also offer drug discount cards for those who meet age and income requirements. Another resource is the non-profit NeedyMeds, an organization that maintains a website about programs that can help people who can’t afford medication. In addition, the U.S. Department of Health and Human Services has a website to help connect people with prescription discount programs. Many pharmaceutical companies offer patient assistance programs for individuals who cannot afford their medications, so look into your options before making a purchase — especially if it’s for a pricey brand name drug.

Read More

What is biofeedback therapy?

Biofeedback therapy involves training patients to control physiological processes such as muscle tension, blood pressure, or heart rate.

These processes usually occur involuntarily, however, patients who receive help from a biofeedback therapist can learn how to completely manipulate them at will.

Biofeedback is typically used to treat chronic pain, urinary incontinence, high blood pressure, tension headache, and migraine headache.

The three most common types of biofeedback therapy are:

• Thermal biofeedback – which measures skin temperature
• Electromyography – measures muscle tension
• Neurofeedback – measures brain wave activity

Biofeedback is particularly effective at treating conditions brought on by severe stress. When a person is stressed, their internal processes such as blood pressure can become irregular. Biofeedback therapy teaches these patients certain relaxation and mental exercises which can alleviate their symptoms.

Therapists can measure a patient’s performance by attaching electrodes to their skin and displaying the processes on a monitor. Eventually patients learn how to control these processes without the need to be monitored.

During a biofeedback session electrodes will be attached to the patient’s skin, which sends information to a monitoring box. The biofeedback therapist reads the measurements and through trial and error singles out mental activities that help regulate the patient’s bodily processes.

Sessions are typically less than an hour long – most people will begin to see positive results after 8 sessions. However, some patients may need a as many as 50 sessions.

Biofeedback for Post-Traumatic Stress Disorder (PTSD). A team at East Carolina University is working toward a portable biofeedback training program that could prevent or reduce PTSD.

What is biofeedback used for?

There is a whole range of health conditions that experts believe can be treated with biofeedback therapy. In fact, it is a very popular choice over drugs, because it does not have any significant risks or cause undesirable side effects.

Other benefits of biofeedback therapy are that it is noninvasive and can be an alternative to medications, which is particularly useful for pregnant women.

Below are some examples of conditions and illnesses that may benefit from biofeedback therapy:

Urinary incontinence

The Agency for Health Care Policy and Research currently recommends biofeedback therapy as an effective form of treatment for urinary incontinence, based on very promising findings in clinical studies.

Children’s anxiety at the dentist’s

Researchers at the Narayana Dental College and Hospital in India set out to determine whether biofeedback therapy might help control children’s anxiety when receiving dental restorations. In the journal European Archives of Paediatric Dentistry they concluded “Biofeedback can be used in the initial visits for dentally anxious children and the usage of simpler biofeedback machines for these appointments in dental setup is suggested.”

Raynaud’s disease

Raynaud’s disease is a condition that causes some parts of the body to feel numb and cool in response to cold temperatures or emotional stress. It is caused by a problem of blood supply to the skin.

Some studies also indicate that thermal biofeedback can help alleviate symptoms of Raynaud’s disease, with reports revealing that 80-90% of patients experienced improved circulation and a reduced frequency of symptoms after therapy.

Chronic constipation

Findings published in the Clinical Gastroenterology and Hepatology, found that biofeedback treatment can successfully retrain muscles which cause chronic constipation.

The lead author of the study said “the study results show that bowel movement improvement is possible in nearly 80 percent of patients through biofeedback.”

Fecal incontinence

Scientists at the University of Lübeck in Germany found that electrical stimulation combined with biofeedback therapy helped patients with fecal incontinence.

They reported in the International Journal of Colorectal Disease that “There is sufficient evidence for the efficacy of BF (biofeedback) plus ES (electrical stimulation) combined in treating fecal incontinence. AM-MF (Amplitude-modulated medium-frequency) stimulation plus BF seems to be the most effective and safe treatment.”

Cognitive and behavioral therapies

Dr. John Krystal, Editor of Biological Psychiatry, said biofeedback may open new avenues for cognitive and behavioral therapies; he was referring to a study that found people can control the activity of certain regions of the brain when they receive feedback signals by functional magnetic resonance brain imaging (fMRI).

Chronic rectal pain

Biofeedback is also more effective than two other treatments for a type of chronic rectal pain called levator ani syndrome, according to researchers at the University of North Carolina at Chapel Hill.

Nocturnal bruxism

Nocturnal bruxism is the clenching, bracing, grinding or gnashing of the teeth and jaws during sleep.

A team at The Turner Dental Hospital, Manchester, UK, explained in the British Dental Journalthat a range of treatment strategies have been used to control nocturnal bruxism, including hypnosis, splint therapy, acupuncture, occlusal equilibration and physical therapy.

Drs. R. Needham and S. J. Davies set out to determine what effect biofeedback might have on nocturnal bruxism. Trial participants were given the Grindcare device, a biofeedback device made by Medotech, and told to wear it every night for five weeks.

Out of the 19 patients in the study, eleven (58%) reported a significant reduction in the occurrence of headaches and jaw-muscle discomfort on waking up in the morning.

The study authors concluded “The use of biofeedback could reduce the level of parafunctional activity and bring about meaningful symptomatic improvement. No adverse effects occurred throughout the study period.”

Read More

Top Cancer-Fighting Foods

Approximately one-third of all cancers are directly related to diet. To help prevent cancer, try making some of these foods that fight cancer a regular part of your diet.

Read More