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New drugs trail many old ones in effectiveness against disease

By Sharon Begley

NEW YORK ' Mon Jun 3, 2013 4:04pm EDT

(Reuters) - Despite the more than $50 billion that U.S. pharmaceutical companies have spent every year since the mid-2000s to discover new medications, drugmakers have barely improved on old standbys developed decades ago.

Research published on Monday showed that the effectiveness of new drugs, as measured by comparing the response of patients on those treatments to those taking a placebo, has plummeted since the 1970s.

While that is already unwelcome news to drug and biotech companies, the consequences for the pharmaceutical industry could get worse under President Barack Obama's healthcare law.

The law established an independent research institute to compare the effectiveness of different treatments for the same condition. That way, patients as well as private insurers and government programs such as Medicare can stop paying for less effective therapies. If the new analysis is correct, then "comparative effectiveness research" could conclude that older drugs, which are more likely to be generics, are better than pricey new brand names that deliver the most profits for drugmakers.

Fears of a crisis in drug innovation have grown over the years. When the healthcare journal Prescrire in 2011 ranked new drugs, only 17 of the 984 developed since 2001 were deemed "a real advance" or better. And a survey of 184 expert physicians in 15 specialties published last month in Nature Reviews Drug Discovery showed the doctors were more likely to rate drugs more than a decade old as "transformative."

To be sure, drugs that completely change outcomes for patients continue to emerge. Gleevec, from Novartis, greatly extends life for leukemia patients, for instance. New antivirals such as Incivek from Vertex Pharmaceuticals have doubled the cure rate in hepatitis C, and Eylea from Regeneron Pharmaceuticals is better than anything previously developed for macular degeneration.

Because of those and other examples, "we believe that a lot continues to be accomplished in terms of yielding very, very positive results for patients, so there seems to be a disconnect between that and this paper," said Randy Burkholder, deputy vice president of policy at the Pharmaceutical Research and Manufacturers of America (PhRMA) trade group.

CANCER TO MENTAL ILLNESS

The new study in the journal Health Affairs examined 315 clinical trials that compared a drug to a placebo and were published in four of the world's top medical journals (BMJ, Journal of the American Medical Association, Lancet and New England Journal of Medicine) from 1966 to 2010. The drugs targeted the full range of human ills, from cardiovascular disease and infections to cancer, mental disorders and respiratory illness.

In the early years, drugs easily beat the placebo: They were, on average, 4.5 times as effective, where effectiveness means how well they lowered blood pressure, vanquished tumors, lifted depression or did whatever else they were intended to.

But the trend line was inexorably downhill, found Dr Mark Olfson of Columbia University and statistician Steven Marcus of the University of Pennsylvania. By the 1980s drugs were less than four times better; by the 1990s, twice as good, and by the 2000s just 36 percent better than a placebo. Since older drugs were much superior to placebo and newer ones only slightly so, that means older drugs were generally more effective than newer ones.

"Their results are pretty compelling," said Dr Aaron Kesselheim of Harvard Medical School, who helped conduct the survey of physicians on "transformative" drugs but was not involved in this study. "It does appear that things are headed in the same direction, with newer drugs having relatively less efficacy."

Experts disagree on why that should be, but suspicions range from the U.S. regulatory process to basic biology.

"It may be that the drug discoveries based on low-hanging fruit were made long ago," said Olfson, as with discoveries based on the most basic or easily targeted causes of high blood pressure. In that case, older drugs based on those targets would pack a bigger punch than newer ones that target less-central causes of disease.

Or, it could be that the patients who volunteer for clinical trials have gotten harder to treat. In many cases, people volunteer because existing drugs are not helping their cancer, schizophrenia or other condition, Olfson said, "and may have forms of the disease where it's harder for a drug to demonstrate a benefit."

Another explanation could be that the scientific quality of clinical trials has improved over the decades, as the Health Affairs analysis found. Human studies in the 2000s were more likely than those in the 1960s to enroll hundreds of patients rather than dozens.

"It may be that the compounds aren't getting less effective but that they're getting looked at more carefully," said Dr Harold Sox of the Dartmouth Institute for Health Policy and Clinical Practice and former editor of the Annals of Internal Medicine.

'SOMETHING REAL IS GOING ON'

While experts agree that tougher trials and similar factors explain some of the decline in drugs' reported effectiveness, "something real is going on here," said Olfson. "Physicians keep saying that many of the new things just aren't working as well," and therefore prescribe antidepressant drugs called tricyclics (developed in the 1950s) instead of SSRIs (from the 1980s), or diuretics (invented in the 1920s) for high blood pressure instead of newer anti-hypertensives.

Whatever the reason for many new drugs packing less punch than old ones, that will not keep them from reaching patients.

"The way the drug regulatory system is set up, even if you have just a small advance, if you market it right it can be very profitable," said Kesselheim.

Critics of the high prices of drugs that are only marginally (if at all) more effective than older, cheaper, often generic medications hope that head-to-head studies will persuade more physicians to stop prescribing expensive but less effective drugs. The Affordable Care Act of 2010 - "Obamacare" - established the Patient Centered Outcomes Research Institute (PCORI) to conduct such comparative effectiveness research.

The drug industry says it isn't worried. "Our sector is not concerned about objective, high-quality patient-centered comparative effectiveness research," said PhRMA's Burkholder. "We believe the substantial value of our products will continue to be demonstrated."

(Reporting by Sharon Begley; Editing by Michele Gershberg and Douglas Royalty)

http://www.reuters.com/article/2013/06/03/us-drugs-effectiveness-idUSBRE95213D20130603

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Heather is the Administrator of the IBS Message Boards. She is the author of Eating for IBS and The First Year: IBS, and the CEO of Heather's Tummy Care. Join her IBS Newsletter. Meet Heather on Facebook!

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Antibiotics Early in Life May Boost Obesity Risk

Published: Aug 17, 2014
By Salynn Boyles, Contributing Writer, MedPage Today
Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

Exposure to antibiotics early in life may permanently alter gut microbes in a way that could increase obesity risk years later, researchers reported.

In a study that compared outcomes in mice given low-dose penicillin versus those who were not, infancy was identified as a critical window of host-microbe metabolic interaction, suggesting that early-life antibiotic exposure can lead to lifelong metabolic changes, wrote Martin Blaser, MD, of NYU Langone Medical Center in New York City, and colleagues in the Aug. 14 issue of Cell.

This new finding expands on previous research by Blaser's group that tied antibiotic treatment from birth to accelerated growth in mice.

"We showed that the earlier we gave the antibiotic, the stronger the effect, and when we combined antibiotics with a high-fat diet the effect was potentiated and the mice got very fat," Blaser told MedPage Today. "We also showed that the metabolic effects remained when antibiotics were given for just 4 weeks in infancy, suggesting that early life exposure can have lifelong effects."

The Antibiotic-Obesity Link

Early life has been shown to be a critical period for metabolic development, and several epidemiological studies suggested a link between early antibiotic exposure to an increase in overweight status later in childhood, the researchers wrote.

Earlier this month, a study published in the International Journal of Obesity found exposure to antibiotics during the first year of life to be associated with a small increase in body mass index (BMI) in boys between the ages of 5 and 12, but not girls.

Blaser's team has studied the impact of antibiotic use on animal and human microbiome and how microbiome alteration impacts health for several years.

Microbes begin to colonize in the gut at birth, and Blaser and colleagues hypothesized that disruption of these communities with antibiotics early in life have long-term effects on weight and the risk for diseases associated with obesity, such as diabetes.

"For decades, farmers have been exposing livestock to low doses of antibiotics to promote growth; the earlier in life that exposure begins the more profound the effects," they wrote.

For the current study, they examined antibiotic exposure timing in an effort to determine if a critical window of exposure exists. They also addressed whether synergies exist between antibiotic exposure and dietary effects, and whether microbiota alterations are sufficient to impact metabolic phenotypes.

"Hypothesizing that early life was the critical period for programming host-microbe metabolic interactions, we sought to determine whether microbiota disruption limited to early life could induce metabolic effects," the researchers wrote. "In addition to long-term (28 week) low-dose penicillin (LDP) or none (control), groups of mice received 4 or 8 weeks of LDP, and to accelerate metabolic phenotypes, all were switched to high-fat diet (HFD) at 6 weeks of age."

Penicillin Altered Ileal Tissue

In female mice, all three low-dose penicillin groups developed elevated total, lean, and fat mass compared to controls, irrespective of low-dose penicillin duration. Compared to controls, following switch to high-fat diet, female low-dose penicillin mice had significantly elevated caloric intake and significantly faster total and fat mass accumulation rates from 6 to 20 weeks of age.

Later in life (weeks 20-28), all three low-dose penicillin groups showed significantly slower rates in lean mass growth compared to controls, indicating catch-up by the control mice.

Male mice on low-dose penicillin showed early elevations in total, lean, and fat mass but did not have increased food intake or feed efficiency from 6 to 8 weeks of age. The early-life changes in body composition were lost with age, which was consistent with an earlier reported increased early-life and gender-dependent sensitivity to high-fat diet that may override microbe-mediated effects, the researchers noted.

"By age 4 weeks, LDP induced substantial histopathologic effects in ileal tissues, notably shortened villi, which is consistent with changed ileal architecture in LDP-mediated livestock growth promotion," the researchers wrote. "Transcriptional profiling analysis of intestinal tissue by microarray and subsequent validation by Nanostring analysis revealed that the ileal atrophy from LDP was associated with a general decreased expression of genes involved in intestinal immune responses, with numerous consistencies across gender."

"Low-dose penicillin decreased expression of genes related to several biological functions, such as differentiation, activation, recruitment, and adhesion of immune cells, and functions specifically related to androgen-presenting cells, T cells, B cells and phagocytic cells," they explained.

High-Fat Diet Exacerbated Changes

Antibiotic exposure also induced numerous compositional changes in the microbiota, and introduction of the high-fat diet had further effects. After antibiotics were stopped in the mice given low-dose penicillin for both 4 and 8 weeks, the patterns associated with high-fat diet exposure of the control mice began to emerge, the group stated, but were never present in mice exposed to 28 weeks of low-dose penicillin.

"The persistent phenotypes after LDP cessation, despite microbiota normalization, provide evidence that the early-life microbiota influences adult body composition," the researchers wrote.

Low-dose penicillin suppressed early-life Lactobacillus, Allobaculum, Rikenellaceae, and Candidatus Arthromitus. This finding suggests a protective role for these organisms in the modulation of host metabolism.

"All microbiota members do not equally impact the host; prior studies indicate that these four organisms have either metabolic and/or immunologic interactions which may contribute to the observed protection from weight gain in the control animals," the researchers wrote.

Future Plans

Blaser's team is currently conducting research designed to determine if re-introducing these bacteria following antibiotic therapy will impact weight gain.

"Our findings imply that restoring good bacteria could prevent the long-term metabolic effects of early antibiotic exposure," stated co-author Laura M. Cox, PhD, in an accompanying statement.

Blaser said some combination of these bacteria or others that have not yet been identified could prove critical in early-life metabolic protection.

He added that the research team is also investigating the impact of early antibiotic use on diabetes risk.

In a prospective study reported earlier this summer, a different group of researchers showed that composition of gut bacteria in patients with type 2 diabetes differed from those of people without the disease.

Obese patients and those with diabetes had lower proportions of the bacteria Firmicutes, Bifidobacteria, and Clostridium Leptum, compared to healthy controls, Yalcin Basaran, MD, of Gulhane Military Medical Academy in Ankara, Turkey, and colleagues reported at the joint meeting of the Endocrine Society and the International Congress on Endocrinology in Chicago.

The analysis revealed that metabolic parameters such as weight (P<0.001), BMI (P<0.001), HbA1c (P=0.011), waist circumference (P<0.001), and fasting blood glucose (P=0.005) were significantly associated with reduced levels of these three types of bacteria in the gut.

Blaser said all of these studies point to an important developmental window early in life during which antibiotic exposure can have long-term effects on metabolism.

"We can't say what this window is, but the epidemiological studies have focused on the first year of life," he said. "Physicians need to know that antibiotics use could have long-term costs, and this needs to be factored into decisions about when to use them."

http://www.medpagetoday.com/Endocrinology/GeneralEndocrinology/47252?xid=nl_mpt_DHE_2014-08-18&utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=ST&eun=g379602d0r&userid=379602&email=heather%40helpforibs.com&mu_id=5372841&utm_term=Daily

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Heather is the Administrator of the IBS Message Boards. She is the author of Eating for IBS and The First Year: IBS, and the CEO of Heather's Tummy Care. Join her IBS Newsletter. Meet Heather on Facebook!

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