FDA Postapproval Studies: ‘You can have pie as long as you do your homework later’

A recent commentary (S Woloshin et al. NEJM 2017; 377: 1114-7) examines the fate of FDA postapproval studies.

“Both Congress and the Food and Drug Administration (FDA) have sought to accelerate the “availability of new drugs by allowing sponsors to wait to resolve many questions about safety and benefit until after their drugs receive marketing approval.”

However, this commentary points out that many times these studies are never completed. The authors examined these studies since 2009.  Key finding:

  • “After 5 to 6 years, 20% of postapproval studies had not been started, 25% were delayed or ongoing, and 54% had been completed.”

The authors note ‘the slow irregular pace of postapproval studies contrasts starkly with the short, rigid deadlines and other shortcuts used to speed marketing approval.”  They suggest that the FDA impose fines and establish shorter deadlines.  They indicate that the current administrations stated view that the FDA is ‘slow and burdensome’ could necessitate even more reliance on postapproval studies by loosening the evidence for new medication approvals.

In the same issue, the FDA responds that there have been improvements and that since 2015, “88% of postmarketing requirements overall…were progressing according to their original schedules.”

My take: More rapid approvals will inevitably lead to more medications with unrecognized safety signals.  These postapproval studies are crucial in identifying infrequent but important adverse effects.

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America Needs Immigrant (Doctors)

While anti-immigrant sentiment has become more widespread among many, in medicine it is clear that immigrant physicians play an important role.  This is discussed in a recent NY Times article: Why America Needs Foreign Medical Graduates

The key points:

  1. Foreign medical graduates help fill residency training positions that would otherwise be left vacant.  Their availability helps many hospitals operate.
  2. Foreign medical graduates disproportionately take positions in primary care, accounting for approximately 40% of primary care physicians.
  3. There is evidence that the care of foreign medical graduates is at least as good as physicians who received their medical degrees in the U.S.

An excerpt:

The American system relies to a surprising extent on foreign medical graduates, most of whom are citizens of other countries when they arrive. By any objective standard, the United States trains far too few physicians to care for all the patients who need them. We rank toward the bottom of developed nations with respect to medical graduates per population…

A 2015 study found that almost a quarter of residents across all fields, and more than a third of residents in subspecialist programs, were foreign medical graduates…

 About a quarter of all doctors in the United States are foreign medical graduates.

My take: Physicians from other countries improve the health of our entire country.  In addition, many physicians who train in the U.S. return abroad and help improve health in their home countries.

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How Many Kids with Reflux Actually Have Reflux?

A terrific recent retrospective study (LB Mahoney, S Nurko, R Rosen. J Pediatr 2017; 189: 86-91) examined how often children with reflux symptoms actually have reflux.

This study reviewed 45 children ≥5 years (mean age 11.8 years) who had undergone both upper endoscopy and impedance pH study (off PPI therapy). Inclusion criteria: no erosive esophagitis. Common symptoms included heartburn, abdominal pain, chest pain, and regurgitation.


  • Nonerosive reflux disease –had abnormal esophageal acid exposure
  • Reflux hypersensitivity -had normal acid exposure but had a positive symptom association to acid or nonacid reflux
  • Functional heartburn -had normal acid exposure and negative symptom association

Key findings:

  • 44% had functional heartburn, 29% with reflux hypersensitivity (27% acid, 2% nonacid), 27% had nonerosive reflux disease (NERD)
  • Response to a proton pump inhibitor (PPI) was not predictive of reflux phenotype: 58% with NERD, 67% with reflux hypersensitivity, and 55% with functional heartburn. Response to PPI was stated as “at least some symptomatic improvement with PPI use.”  There was not a difference in PPI response among those who received a dose <1 mg/kg and those ≥1 mg/kg.
  • Microscopic esophagitis was present in 17% in NERD, 25% with reflux hypersensitivity, and in 20% of functional heartburn

While this study has limitations, including referral bias, it is likely that these patients are typical for many pediatric gastroenterologists. The authors note that typical patients were “patients who underwent a PPI trial but continued to have persistent symptoms.”

My take: In a pediatric gastroenterology setting, the most common reason for “reflux” is actually functional heartburn.  Thus, in those with persistent symptoms, evaluation with endoscopy and pH probe is worthwhile, especially as there has been more attention to potential risks of PPI therapy.

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View from Asheville, NC

Moving Away from Liver Biopsies

A recent review (EB Tapper, AS-F Lok. NEJM 2017; 377: 756-68) provides a good review of liver biopsy and liver imaging. My take of this review is that it highlights the emergence of noninvasive tools (imaging & fibrosis markers) which may supplant liver biopsy.  This article does not delve into how more widespread genetic testing may obviate a liver biopsy in many cases as well. The article notes that about 8% of persons in the U.S. have elevated liver enzymes.

Liver biopsy:

  • “A typical liver biopsy samples one fifty-thousandth of the liver.”
  • Limitations of liver biopsy: sampling error is common, biopsy interpretation is subjective, and biopsies can cause complications.  Pain is noted in 30-50% of patients, serious bleeding in 0.6%, injury to other organs (0.08%), and in rare cases, death (up  to 0.1%).
  • Cost: “the average direct cost of a percutaneous liver biopsy is $1448 (in 2016 U.S. dollars).” Transjugular biopsies are much more expensive.  In addition, there are unmeasured indirect costs, due to missing work.

Some prior blogs on liver biopsy

Blood tests:

  • The article details the formulas for biomarker measurements that predict the risk of fibrosis, inlcuding FIB-4, Lok Index, and NAFLD Fibrosis Score.
  • In most liver diseases, aspartate aminotransferase levels “exceed alanine aminotransferase levels when cirrhosis develops.”
  • Thrombocytopenia “is the earliest indicator of cirrhosis among routine blood tests…[due to] diminished liver function (throbopoietin underproduction) and portal hypertension (splenic sequestration).”
  • Proprietary algorithms to assess fibrosis have variable sensitivity, specificity –include FibroTest (aka FibroSure [LabCorp]), FibroMeter, HepaScore (Quest), FIBROSpect, and the Enhanced Liver Fibrosis Score.


  • Elastography with vibration-controlled transient elastography (VCTE) OR magnetic resonance elastography
  • “Elastography offers excellent negative likelihood ratios for advanced fibrosis but much poorer positive likelihood ratios.”
  • Patients with severe obesity are less likely to obtain adequate study with VCTE and could need magnetic resonance elastography to assess fibrosis.

My take: Noninvasive tests have already sharply reduced the need for liver biopsy.

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Physician Team Cohesiveness

Recently, I attended our medical staff semi-annual meeting.  Two speakers (Dr. Usha Sathian and Dr. Lucky Jain) provided some impressive information about the growth of the hospital system’s outreach with ambulatory care services and about the development of Emory/associated institutions’ academic medicine advances.  The latter includes graduate medical education, extensive grants, and involvement in more than 1000 current clinical studies.  The number of trainees at all levels has grown incredibly.  These trainees are much more likely to stay in Georgia than trainees in many other parts of the country.

This growth corresponds to increases in the hospital’s bed capacity and technical abilities.  A third speaker, Dr. Joseph Rosenfeld, was honored for being both a community physician and attending physician for 40 years!  When he first arrived, there were eight pediatric ICU beds at Egleston Children’s hospital.  Now, there has been about an 8-fold increase.  The number of hospital beds has more than tripled.

Yet, sadly in my view, only a tiny number of physicians attended this meeting, a fraction that attended when the medical staff was much smaller.  Despite the huge increase in staff physicians, there is a dwindling number who attend meetings; this is true for grand rounds as well.  When I first arrived in town about 20 years ago, I looked forward to these meetings to engage and meet my colleagues.  In addition, due to ever larger number of subspecialists, it is much less frequent that when I rotate on hospital service that I will see the well-known neurologist, pulmonologist, endocrinologist, infectious disease expert and so many others.

I came away from the staff meeting with a tangible feeling that despite the incredible success of the system in developing improved capabilities that the feeling of working together as a team of subspecialists and generalists has diminished.  This makes me wonder whether other aspects of modern medicine and the worry over physician burnout are not related to increased isolation of physicians into their specialty silos and to cloistering into our computers and smartphones.

Though I feel grateful to be able to help children in my work, the biggest reason that I chose pediatrics was because of my admiration for the pediatricians I had met and my desire to both emulate their work and to work with them.  I think working closely together is one aspect that makes being a pediatric specialist worthwhile.

My take: Experts have recommended “peer support” to prevent burnout and increase job satisfaction.  My experience, which I suspect is shared widely, indicates that engaging with our peers is becoming less frequent.

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Drug Development for Eosinophilic Esophagitis

Full text link: White Paper AGA: Drug Development for Eosinophilic Esophagitis (EoE)

I Hirano et al. Clin Gastroenterol Hepatol 2017; 15: 1173-83. This article reviews diagnostic criteria for EoE, clinical endpoints, and current/emerging treatments.

From AGA website-an excerpt:

Four important points from the white paper:

1. There is a complex inter-relationship between EoE, gastroesophageal reflux disease (GERD) and proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE). A substantial proportion of patients with esophageal eosinophilia will improve with PPI treatment.

2. The clinical features and presentation of EoE differ between children and adults. Poor symptom specificity among children has limited the ability to identify appropriate candidates for enrollment into clinical trials and has impeded the development of pediatric patient-reported outcome instruments.

3. Aside from pharmacologic approaches, EoE can be addressed with dietary modifications and/or endoscopic dilation.

4. We should remember that the diagnosis of EoE carries a potentially major financial burden on patients’ families, making identifying new, effective and affordable treatment options a priority.

Great Story -How CAR-T Came About

While chimeric antigen receptor T-cell (CAR-T) therapy does not have much to do with pediatric gastroenterology, the development of this therapy, described recently (L Rosenbaum NEJM 2017; 377: 1313-5), holds lessons about perseverance and chance that are widely applicable.

CAR-T involves genetically engineering the patient’s own T cells to kill tumor cells. It recently received FDA approval to treat patients up to 25 years of age with relapsed or refractory acute lymphoblastic leukemia.

The story of the survival of Emily Whitehead, the index patient for this therapy, is suitable for Hollywood.  The groundwork for this very expensive treatment dates back to 1893 with William Coley’s recognition of the immune system’s potential for treating cancer –he injected streptococcus into an inoperable osteosarcoma and observed tumor shrinkage.

Key Steps in this Story:

  1. University of Pennsylvania’s immunologist Carl June spent his career working on CAR-T. His wife died of ovarian cancer in 2001 and he resolved to develop this emerging immunotherapy that he had wanted for her.
  2. Barbara and Edward Netter provided key funding for this project in 2008.  They too had lost a close family member to cancer.
  3. Emily Whitehead nearly died due to CAR-T therapy which triggered cytokine-release syndrome, which was not a recognized entity at the time.  In part due to chance, extremely high levels (>1000-fold) of interleukin-6 (IL-6) were detected quickly due to the ability of the institution and prodding by the researchers to their colleagues.  This allowed the experimental use of tocilizumab, a monoclonal antibody that targets IL-6.
  4. Her survival helped reenergize this line of research.

My take (borrowed from author): “Therapeutic advances are motivated by more than money –that it’s the hope, vision, and perseverance of both patients and investigators that made this …possible.”

Acute esophageal necrosis ina a 63 year-old that resolved with conservative treatment.  “The cause is unknown..[it] occurs most commonly in the distal third of the esophagus, which is hypovascular” often in the setting of chronic disease.