Sunday, October 9, 2016

FDA Documents Prove: "Clinical Utility" Was Not Just Invented Recently

Hardly a conference passes without someone saying that today, diagnostic tests require "clinical utility," but this wasn't required until recently.
  • If it's a 1995 conference, clinical utility is recent, being required since 1990.   
  • If it's a 2015 conference, clinical utility is recent, being required since about 2010.   
  • It's a rolling date.   
I was in medical school in the mid 1980s and we were regularly taught, do not order a medical test unless it's medically necessary, and unless there is some action that will pivot on the test.

Lest us human artifacts of the 1980s be criticized for imaginative memory, Richard Ablin provides some extensive documentation in his book, "The Great Prostate Hoax" (St. Martin's Press, 2014.)   Ablin led the discovery and purification of the PSA protein, which was later developed into the clinical PSA immunoassay by others.  Ablin is on faculty at University of Arizona; he is known for a 2010 New York Times op-ed highly critical of PSA testing, and his concerns are documented at length in his 2014 book.  [More about Ablin's book and related citations, at bottom.]   He documents at length the active, even heated, debates over the clinical utility of PSA testing in 1985 and in 1993, based on his access to contemporary transcripts.

(Continues after break.)

The 1985 PSA Ad Comm

While Ablin has lived through the entire PSA era, he also conducted extensive documentation research and interviews for his book.  In particular, he had access to FDA advisory committee transcripts for the original approval of PSA as a cancer monitoring (recurrence) test - on December 8, 1985, in room 703-727A of the Humphrey Building in DC, as Ablin informs us.   (The transcript isn't available online, as far as I can tell.  Ablin suggests the documents were obtained under FOIA for his book [p. 222].)

The PSA immunoassay was developed by a cutting-edge San Diego biotech company called Hybritech.  Ablin discusses the Ad Comm as struggling with "scrambled pieces of evidence" and sees the panelists as vocal and highly critical of whether the test had been shown to have clinical utility - whether the PSA test was clinically useful.  (This panel is described in detail, with extensive quotations, in Amblin's book at page 28ff.)

Panelists complain, "The clinical relevance was less apparent...If PSA is to give us a useful marker...we can't do anything with it."

There was also a discussion of the relative validity of prospective versus retrospective data (retrospective data was being presented, but Ablin's thinks the panelists were confused about this until "page 86 of a 107-page transcript.")

The 1993 PSA Ad Comm

Ablin provides us with even more journalistic detail and quotes based on the second FDA meeting on PSA in 1993.  which was to add a screening indication to the "monitoring" indication.  The ad-comm was held "on June 29, 1993, an unseasonably warm Tuesday, in the Plaza I Ballroom of the Holiday Inn Crown Plaza in Rockville." (page 64 ff).   Again, the PSA labeling change was the subject of a vigorous, hotly contested workday, with much debate on the quality and range of the existing data, whether it supported new labeling claims, and whether the new indication would improve net health outcomes.

A contemporary 1993 New York Times article by Gina Kolata also describes the FDA PSA meeting as hotly contested (NYT).

So We Can Conclude Today That....

Asking whether tests improve health outcomes before deploying them was hardly invented in the last 5 years.


Other Collateral on the PSA Topic

Beyond Ablin's 2010 NYT editorial, cited above.  For a 2010 Roswell Park webpage on the topic, in response to Ablin in the NYT and NPR, see here.   A 2013 article by Ablin appeared in ASCO POST, here.  A 2014 article at Medscape, triggered by Ablin's book, was co-authored with Eric Topol - here.  Ablin also had a second op-ed in 2014 in the NYT, here.

For a "Letter to the Editor" from Mohler &  Donald Trump - the Donald Trump MD who headed Roswell Park Cancer Institute - see here.

Although not the first FDA document invovling the expansion to screening, a 1998 update of the FDA PMA is here.  To my knowledge, the 1990's meeting materials and transcripts aren't available online (FDA  posts those documents from 2005 forward).  Dr, Steve Gutman, who worked in diagnostics at FDA from 1992 to 2009, recalls the 1993 argumentation; he was later head of the division for diagnostics approvals.

PSA as a Medicare Benefit

While Ablin is very strongly opposed to PSA screening, and views prostate cancer care as a medical-industrial complex, he does not mention the story behind instantiating PSA screening as a Medicare benefit.   This occurred in the Balanced Budget Act of 1997, section 4103, and implementational CMS rulemaking at 64 Fed Reg 59480-59590, specifically 59414ff, November 2, 1999.  (Colon cancer screening, mammography, and PAP smears were added to Medicare in the same year.)

Ablin probably could have devoted a colorful chapter to the story of this Medicare activity, but didn't go down this road.   (I ran across a public law for PSA screening in Maine, 1998, suggesting that at the time there was both state and federal lobbying underway.)

Ablin's Book as a Whole

I wouldn't attempt a review of Ablin's book; he devoted impressive research and journalistic skills in documenting a decades-long story.   He repeated states that PSA isn't specific for cancer - but medical and public health readers know that screening tests usually aren't, such as mammography, FOBT colon cancer testing, PAP smear tests, and so on.

He is quite critical, late in the book, of tests that attempt to refine, scope and target prostate management - Myriad Prolaris, Opko 4KScore, and others.  This seems overcritical to me - like he can't turn his gun off - if we could in fact reduce unecessary biopsies in half, or manage low risk cases three times better, etc, this would surely be a public good for a cancer that is in the top 2 or 3 leading causes of male death from cancer (lung, colon, prostate, thus colon/prostate if you don't smoke.)


At a genomics conference in Berlin in October 2016, I saw a reference to Ablin's book by Stephen Pennington, professor of biomedical proteomics in Dublin, and read the Ablin book as ebook on the
next day's flight back to the US.

For an earlier blog, that Medicare "Coverage with Evidence Development" actually traces to the early 1980s, see here.

Not really to PSA, but for other references to the state of technology assessment of diagnostics in the 1970s and 1980s, see "High Technology Medicine: Benefits and Burdens" by Bryan Jennett (1986).  Available used for $2 on Amazon.  Describes skeptics and negative outcome studies in the earliest days of another diagnostic test, CT imaging.   Jennett was an extremely interesting guy, a British neurosurgeon who was passed over for promotion more than once early in his career but became one of the best known academics of his day.  He wrote foundational work on vegetative brain states and co-led the development of the Glasgow Coma Scale.  He was also a productive author on medical customs, public health, technology assessment.   Early in his career Jennett kept exhaustive systematic records on file cards and he was an early, early adopter of computerizing them in the 1970s..."on tape."  So he was also a pioneer of "big data in healthcare" for that era.  He won the first career achievement award of the British Neurological Society and was a Rock Carling Fellow, a British award for  work on healthcare reform that dates to 1964.  The current Rock Carling Fellow is Alan Garber; others have including Archie Cochrane and Alain Enthoven.  

See also Jennert's slightly earlier 1984 essay on rationing of hospital care in "The Painful Prescription," eds. Aaron & Schwartz, here.

For an FDA posting (without documents) of PMA 920030, here.  the FDA appears to note that PMA was submitted 1992, approved 1998.  For a year 1998/2000 update with full PDFs for approval order, summary of effectiveness, and labeling, see here.  (The approval order on a 12/8/1998 is signed by Steven Gutman, here.)