Tales from the FDA Crypt
In the late winter of 1999-2000, I was still working at FDA. More and more of my time was being taken by my attempts to understand what was known about cardiac repolarization. As described elsewhere on this site, FDA needed (and still needs) to catch up with the electrophysiology community in this area. I enjoyed this work, but I was also looking forward to my April 2000 trip to Nepal, when I would walk with my friend Peter Reuter from Tansen through Dhorpatan to Beni. My reserved flights to and from Kathmandu went through London.
In February, I was invited to speak at an academic repolarization meeting in London, to be held the day before I was already scheduled to change planes at Heathrow. It seemed efficient: I could leave a day or two earlier, attend the meeting, and then continue eastward.
My invitation to the meeting was accompanied by routine guarantees of business-class airfare and an honorarium. The honorarium could not be accepted, of course. Also, FDA employees travel in the style to which FDA accustoms them; FDA will accept reimbursement of travel costs, but only for travel in the back of the plane.
I had anticipated those restrictions, and I submitted a request for two travel days to the appropriate office. Then I learned of another restriction: Foreign business travel may never be adjacent to personal leave. As an accommodation, I might be allowed to attend the meeting in London, fly back to the US, and then (without leaving the airport) immediately fly back to London to catch my ongoing flight to Kathmandu. Approval for that arrangement was not guaranteed.
I declined the invitation. When I got back from Nepal, I was still interested in the then-hot topic of drug effects on repolarization, so I retired from FDA.
The CDER mission statement
Shortly after taking office as Director of the Center for Drug Evaluation and Research, Janet Woodcock started assigning people to work on a Mission Statement. Later, most supervisory employees spent two or three days at a private conference center in Virginia, working on the statement.
We had all heard of mission statements before, but we thought they could appear only as excrescences of corporate bureaucracy. Not so. But then, perhaps mission statements could serve a different purpose in government from that that they served in the private sector.
Well, yes, but the difference is not favorable. If you ran a company of mass-market saddlemakers 100 years ago, you might have felt pressed to ask yourself what the core of your business was. Was your mission to sell saddles, so the business should adjust from mass production toward being a boutique for the horsy set? Was your mission to work in leather, so the business might branch out from saddles to purses and wallets? Was your mission to facilitate transportation, so that you might start making tires or steering wheels? Your mission was yours to choose.
Federal agencies do not choose their missions. David Kessler at one time decided that the FDA's mission included the regulation of tobacco, but the Supreme Court ruled that it didn't. FDA (and others) might believe that the FDA's mission includes the regulation of so-called supplements, but Congress has said that it doesn't. CDER's mission-statement exercise would have been an embarrassment, even if it had produced a substantive text. It didn't.
Some Center employees simply never showed up at the multi-day mission-statement meeting, some (including me) left during the first lunch break, but most of them stuck it out. A few weeks later, expensively-printed copies of the Mission Statement appeared on the walls of various non-scientific offices in the Center. No one, in my experience, ever respectfully referred to it.
Janet Woodcock may have made other contributions as Center Director, but the Mission Statement is the only one I remember.
Press releases and talk papers
As an entity within the Department of Health and Human Services, FDA has no independent authority to issue press releases. An FDA document intended to be a press release must be passed through politicos at the Department level, with predictable loss of timeliness and unpredictable retention of content. FDA copes with this structure by having a Press Office that issues documents that resemble press releases, but the documents are called Talk Papers.
During my tenure at FDA, the FDA's Press Office was staffed, at least in part, by people whose English skills were spotty. With the announced goal of simplifying overly-technical language provided by the Division, they rewrote our draft Talk Papers into words that were arguably simpler, but often ungrammatical, and almost always misleading as to points that we had taken pains to get right. In 1998, I went through several rounds of correcting the spelling, grammar, and meaning of their "simplification" of a then-forthcoming Talk Paper about the withdrawal of mibefradil. In extremis, I produced a version written entirely, except for the drug and company names, in words of one syllable.
It was the best of Times, it was the worst of Times, but not in that order
I was one of many FDA-associated people interviewed by a Los Angeles Times reporter doing a series on recent drug withdrawals. When the series appeared on 20 December 2000, I realized that he and I had not talked about many of the key concepts behind modern pharmacotherapy, drug development, and drug regulation. Some of these concepts are non-obvious, as demonstrated by both the thrust of the articles themselves and by some of the quotes that the author gathered from FDA insiders & outsiders. I felt compelled to send the author a long email message. The posted email message led to an interview with Denise Grady and an article in the New York Times on 6 March 2001.
Drug-induced changes in cardiac repolarization
Some of FDA's shambolic approach to these matters is described elsewhere.
How drugs are approved for marketing in the United States
As an expert witness in a product-liability case that was settled in 2011, I prepared a number of expert statements. One portion of one of these statements dealt with how drugs are approved for marketing in the United States. The period of interest then was 1990-2006, so some of the details have changed, but most of what I wrote is still correct.
How antihypertensive drugs are approved for marketing in the United States
I contributed chapters on this topic to the first and second editions of Oparil & Weber's Hypertension (Philadelphia: Saunders and then Elsevier Saunders, 2000 and 2005). Not much of my text changed between editions, but the paragraphs
Applications for new antihypertensive drug products come to the FDA's Division of Cardio-Renal Drug Products (DCRDP). As of early 1998, the staff of DCRDP included 18 physicians, 15 toxicologists, and 11 administrative and technical personnel. In addition, there were at that time 11 chemists, 6 biopharmaceutical reviewers, and 6 statisticians who — although not formally members of DCRDP — were assigned full-time to the support of the Division.
. . .
A Nonapprovable letter must describe the deficiencies in the application that led to the Agency's negative conclusion.
At the other extreme, an Approval letter is usually short and simple. The third type of Action Letter, the Approvable letter,
is used for a product which appears to be safe and effective, but with respect to which there remain minor gaps in the
chemistry description, unsettled portions of labeling, or other deficiencies that appear to be straightforwardly reparable.
Marketing of the product is not permitted until the issuance of an Approval letter.
were updated to
Applications for new antihypertensive drug products come
to the FDA's Division of Cardio-Renal Drug Products (DCRDP). As of late 2003, the staff of DCRDP included
physicians (down from 16 in
1999), 13 toxicologists (down
from 15), and 12
administrative and technical personnel (up
from 11). In addition, there
were at that time 8
biopharmaceutical reviewers, and 5 statisticians who — although
not formally members of DCRDP —
were assigned full-time to the support of the Division.
. . .
The third type of Action Letter, the
Approvable letter, was
originally used for products
to be safe and effective, but with respect to which there remained
minor gaps in the chemistry description, unsettled portions of labeling, or
other deficiencies that appeared
to be straightforwardly reparable.
The typical Approvable letter was then followed by no more than a few weeks of
faxes and meetings before the predictable appearance of an Approval letter.
More recently, apparently as a response to time constraints imposed upon the
Agency by the Prescription Drug User Fee Act, Approvable letters have been less
closely coupled to ultimate approval.
The total elapsed time from the Division's
receipt of the application to its issuance of the Action Letter averaged
about 14 months in
the late 1990s. The Division declines to release any newer statistics, and
such statistics would in any event be difficult to interpret, in view of recent
changes in the use of Approvable letters.
Page revised: 06/10/2018 21:22