“Reference Pricing” to Improve Costs in Medication Selection

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A recent study (JC Robinson et al. NEJM 2017; 377: 658-65) examined the topic of “reference pricing” and how this could be used to lower costs of medication usage.

“Under reference pricing, the insurer or employer establishes a maximum contribution it will make toward the price of a drug or procedure, and the patient pays the remainder.”

In this study, the authors examined 1302 drugs and more than 1.1 million prescriptions (2010-2014). Specifically, the authors compared RETA Trust, a national association of 55 Catholic organizations, which implemented reference pricing and compared costs with  a labor union that maintained a drug formulary with copayments similar to RETA Trust but did not implement reference pricing. Key findings:

  • “Implementation of reference pricing was associated with a higher percentage of prescriptions that were filled for the lowest-priced reference drug within its therapeutic class” (increase in 7%) along with a lower average price paid per prescription (-13.9%) than the comparison group.
  • Reference pricing was associated with increase in copayment by patients (5.2%)
  • Reference pricing was associated with reduced spending for employers by $1.34 million and increase in copays for employees by $0.12 million than in the comparison group.

Reference pricing has been associated with decreases of 10-12% in medication costs in European nations, as well.

The authors conclude: “Reference pricing may be one instrument for influencing drug choices by patients…pharmaceutical manufacturers who wish to charge premium prices may need to supply evidence of commensurately premium performance.”

My take: Although in concept reference pricing makes sense, I do worry that patients may be pushed towards less effective medications as not all medications in the same class are equally-effective.

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This graph shows the percentages of prescriptions for the lowest-priced drugs before and after implementation of reference pricing for RETA Trust. Union Trust is the comparison control.

How Healthy are “Healthy Volunteers?”

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A recent study (V Takyar et al. Hepatology 2017; 66: 825-33) examined a total of 3160 subjects enrolled in 149 clinical trials from 2011-2015.  These patients were derived from the NIH Clinical Center, ≥18 years, had ALT and BMI measurements available. Presumed NAFLD (nonalcoholic fatty liver disease) was classified if patient had elevated ALT (≥20 for women and 31≥ for men) along with BMI >25 kg/m-squared.

Key findings:

  • 27.9% (n=881) of these healthy volunteers had presumed NAFLD.  These patients also had higher triglycerides, low-density lipoprotein, cholesterol and HbA1c (P<0.001 for all)
  • The authors note that the presence of these presumed NAFLD as controls “likely” affected the study validity in 10 studies and “probably” affected another 41 studies.

My take: This study shows that patients with presumed NAFLD are often enrolled in research studies as healthy controls.  Furthermore, this can affect study outcomes.

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Outcomes of Children Whose Mothers Have Inflammatory Bowel Disease

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A recent study (LR Jolving et al. Inflamm Bowel Dis 2017; 23: 1440-46) used a nationwide (Denmark) register-based cohort to examine the health outcomes of children whose mothers have inflammatory bowel disease (IBD).  This cohort of 9238 children were compared with nearly 1.4 million children born to women without IBD. Median follow-up time was 9.7 years of the children whose mothers had IBD.

Key findings:

  • Hazard ratio for developing IBD in the offspring was 4.63 if maternal ulcerative colitis
  • Hazard ratio for developing IBD in the offspring was 7.70 if maternal Crohn’s disease
  • “Our data otherwise do not provide evidence for an increased risk of any of the other examined diseases in the offspring.” This included diabetes mellitus, thyroid diseases, rheumatoid arthritis, epilepsy, chronic lung disease, mood disorders, schizophrenia, epilepsy, and anxiety disorders.

Raw numbers for developing IBD:

My take: This study documents the expected finding of an increased risk of IBD among the offspring of women with IBD. No other chronic diseases were increased in this study.

Briefly noted: SM Yoon et al. Inflamm Bowel Dis 2017; 23: 1382-93.  This retrospective registry study included the following:

  • 314 subjects with Crohn’s disease (CD) who were primary nonresponders, and 179 with CD who were secondary nonresponders
  • 145 subjects with ulcerative colitis (UC) who were primary nonresponders and 74 with UC who were secondary nonresponders

Key findings: “Colonic involvement (OR 8.0) and anti-TNF monotherapy (OR 4.9) were associated with primary nonresponse to anti-TNF agents in CD.” Higher ANCA levels in UC (HR 1.6) were associated with time to loss of response to anti-TNF agents.

 

Combination Therapy with Adalimumab -Is it Helpful?

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A recent study (JM Chalbhoub et al. Inflamm Bowel Dis 2017; 23: 1316-27) performed a systematic review and meta-analysis to examine the effectiveness of Adalimumab (ADA) combination therapy compared with monotherapy.  With infliximab (IFX), the SONIC study, showed that combination therapy with an immunomodulator (IMM) (azathioprine) improved response; combination therapy resulted in reduced immunogenicity, lower rates of infusion reactions, and higher IFX levels.

With the advent of widespread use of therapeutic drug monitoring, some have questioned the need for combination therapy with IFX.  The need for combination therapy for ADA is also a matter of debate.  ADA has less immunogenicity than IFX and it is unclear if combination therapy will improve outcomes. There have been conflicting studies regarding combination therapy with ADA, prompting the current meta-analysis.

The authors identified 24 articles for inclusion from an initial pool of 1194. Key findings:

  • No significant difference between combination therapy and monotherapy was noted for induction of remission (OR 0.86) or response (OR 1.01). The induction of remission is based on data from 3096 patients (1400 on combination treatment).
  • No difference was noted for maintenance of remission (OR 0.97) or response (OR 0.91). The maintenance of remission is based on data from 1885 patients (859 on combination treatment).
  • Patients receiving combination therapy had lower odds of developing antidrug antibodies (OR 0.24)
  • Subgroup analysis in anti-TNF experienced patients showed improved successful induction of remission (OR 1.26) but also more frequent opportunistic infections (OR 2.44)

Overall, the authors conclude that “combination of ADA and immunomodulators does not seem superior to ADA monotherapy for induction and maintenance of remission and response to Crohn’s disease.” They do comment on the recent DIAMOND study which was a randomized open-label top-down strategy trial in anti-TNF-naive and IMM-naïve patients.  While no overall advantage of combination therapy was evident, better endoscopic response (84% vs. 64% with monotherapy) was seen at 26 weeks (but not at 52 weeks).

This study has several limitations.  Overall, there were a small number of randomized trials and the trials had significant heterogeneity.

My take (borrowed from authors): “It is unclear whether the addition of IMM impacts the efficacy of a less immunogenic anti-TNF biologic such as ADA in CD.” Though, in the subgroup of anti-TNF exposed patients, “combination therapy was associated with higher odds of induction of remission.”

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Somewhat Funny Flatulent Research

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A recent study (CV Almario et al. Clin Gastroenterol Hepatol 2017; 15: 1308-10) was titled: “Old Farts -Fact or Fiction?  Results from a Population-Based Survey of 16,000 Americans Examining the Association Between Age and Flatus.” I was surprised that this was not in an April Fools edition, though I had to read the article because of the intriguing title. The authors premise was to determine if the elderly pass more flatus.

Key findings:

  • Based on self-reporting using a mobile app (MyGiHealth), the authors found that individuals ≥65 years passed flatus less often than the younger age groups. Among those reporting flatulence every 1-2 hours, only 22.6% of those ≥65 years had this frequency; this compared to at least 33% in all other age groups.
  • Most commonly, individuals in all age groups reported passing flatus about every 3-4 hours (36-41%); the next most common frequency was about every 1-2 hours (23-38%) across all age groups. The other frequent category was passing flatus once or twice a day which was reported between 24-29% across all age groups.

The authors indicate that limitations of their study include “social desirability bias” and “information bias.”  In addition, while the entire cohort was >16,000, there were only 296 who were ≥65 years of age.

While I’m not an expert in this field, other limitations could include worsened ability to detect/record flatus with age and/or worsened memory about frequency of passing flatus.

My take: This study shows that almost any study could find a home in some medical journals. In my view, self-reported frequency of passing flatus may not be accurate (the dog did it!).

Pitt Street Bridge, Charleston, SC

An Allergy-Immunology View of GI Diseases

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Recently, one of our allergy-immunology colleagues, Dr. Kiran Patel, from Emory presented an update on GI Diseases from an allergist viewpoint at one of our GI clinical education meetings. With his permission, many of the slides are noted below.  The slides present a good deal of information, though a lot of nuance and further details were provided by Dr. Patel.

Next few slides discuss typical GI food allergies.  It is not surprising that a lot of allergies manifest with GI symptoms given the amount of immune cells in the intestines and frequent interactions with foods and antigens.

This next slide points out that four of the most common food allergens (cow’s milk, egg, soy, and wheat) are frequently outgrown, whereas with peanuts, tree nuts, fish, and shellfish, it is uncommon to outgrow these allergies..

The next slide discusses potential evaluation.  While the slide states that the positive predictive value of skin prick tests and serum-based IgE tests may be as high as 50%; in fact, when broad panels of allergy tests are ordered, the positive predictive value can be quite low.

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Dr. Patel did discuss the LEAP study and the LEAP-ON study which overall indicate that early antigen introduction is likely to reduce food allergies. Related blog posts:

 

The next few slides review Food Protein-Induced Enterocolitis Syndrome. Related blog posts:

The next few slides discuss eosinophilic esophagitis (EoE).  Allergy testing has not been very helpful in most patients with EoE. Related blog posts:

The last part of Dr. Patel’s talk focused on GI disease (eg. inflammatory bowel disease presentation) of primary immune deficiencies.  In the bottom slide, the diseases that often present with GI symptoms are boxed.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and changes in diet should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Big Study of Primary Sclerosing Cholangitis -Pediatrics 2017

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In July, this blog reviewed a recent big study of primary sclerosing cholangitis (PSC) in adults with more than 7000 patients. A recent study in the pediatric age group enrolled 781 children from 36 institutions: MR Deneau et al. Hepatology 2017; 66: 518-27 (Congratulations to Nitika Gupta and Miriam Vos -in-town colleagues and contributing authors to this study.)

This retrospective study’s key findings:

  • Median age 12 years at diagnosis; 39% were female
  • Autoimmune hepatitis (overlap) was present in 33%
  • Small-duct PSC was present in 13%
  • Inflammatory bowel disease (IBD) was present in 76%
  • PSC-IBD and Small-duct PSC (normal cholangiograms) had more favorable prognosis with hazard ratio of 0.6 of developing complications
  • Portal hypertensive and biliary complications were noted in 38% and 25% respectively. After developing these complications, the median survival with native liver was 2.8 years and 3.5 years respectively
  • Survival with native liver was noted in 70% at 5 years and 53% at 10 years
  • Elevations in bilirubin, GGT, and AST-to-platelet count ratio were associated with highest risk of progressive disease.
  • Cholangiocarcinoma (CCA) developed in 1% (median, 6 years after diagnosis)

The discussion notes that while pediatric PSC is a progressive disease, complications were slower to develop compared with adult-onset PSC. 10-year survival with native liver is typically lower in adults ~60% (vs 70% in this study).  “Up to one third of adults with PSC may have esophageal varices within a year of diagnosis” compared with only 13% in this cohort.  Dominant strictures are more common in adults, occurring in the majority within 5 years whereas this occurred in 16% of this cohort.

With regard to CCA, the authors note that current recommendations suggest starting to screen for CCA in patients over age 18 years with ultrasound and CA 19-9 at 6-12 month intervals. These studies “could reasonably be extended to PSC patients aged 15 and above and [for those requiring dilatation] of biliary strictures.”

My take: This large pediatric PSC study provides more clarity on the outcomes of patient’s with PSC and the associated conditions.

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Updated Biliary Atresia Epidemiology

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A recent retrospective study (PC Hopkins, N Yazigi, CM Nylund. J Pediatr 2017; 187: 253-7) provides an update on the recent incidence of biliary atresia in the US from 1997-2012. This study relied on coding for biliary atresia or Kasai hepatoportoenterostomy to identify cases using HCUP-KID database.  This database provides a nationally representative sample of pediatric hospitalizations and captures ~96% of pediatric hospitalizations in the US.

Key findings:

  • Incidence of biliary atresia (BA) was 4.47 per 100,000 (1 in 22,371 infants)
  • BA was more common in females (RR 1.43), Asian/Pacific Islanders (RR 1.89), and blacks (RR 1.30)
  • Median age at the time of the Kasai procedure was 63 days with no improvement over the course of the study period.  More than 50% of all children underwent the Kasai procedure after the optimal window of 60 days of life

My take: In my view, at this time, obtaining a blood test for direct bilirubin in the first two weeks of life will need to be adopted broadly if we are going to diagnose biliary atresia at an earlier age.

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Dry Falls, Highlands NC

Dry Falls, Highlands NC