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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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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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.

We Are Last in Health Care Among High-Income Countries

In a recent commentary (EC Schneider, D Squires. NEJM 2017; 377: 901—4) explains why the U.S. Health Care System is last among high-income countries.

Overall, the U.S. “begins with a challenge: its population is sicker and has higher mortality than those of other high-income countries.”  The U.S. has a rate of death from “conditions that can be managed and treated effectively (referred to as ‘mortality amenable to health care’) is far higher than in other high-income countries.

Four areas that have to be addressed to help U.S. move from last to first:

  • U.S. must confront lack of access to health care. The top-ranked countries offer universal insurance coverage with minimal out-of-pocket costs for preventive and primary care.
  • Underinvestment in primary care. In other countries, a higher percentage of “the professional workforce is dedicated to primary care than to specialty care.”
  • Administrative inefficiency. “Both patients and professionals In the United States are baffled by the complexity of obtaining care and paying for it.”
  • Disparities in the delivery of care. This may be mediated in part by a less robust social safety net than other high-income countries.  “Social spending [for] stable housing, educational opportunities, nutrition, and transportation may reduce the demand for” many health care services.

My take: It makes me mad that our health care system performs so poorly compared to other countries.

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Firearm Mortality -Tragic Inertia

When it comes to gun violence, the U.S. is the leader among developed nations.  It is sad how that despite the magnitude of this problem there are not significant efforts to mitigate this tragedy.

We know from Australia’s experience that changes in gun laws can make a big difference: Link: Gun Law Reforms and Firearm Mortality, Australia 1979-2013

Politico report: The gun lobby: See how much your representative gets

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