Microsoft word - response to angell review.docx

I agree with Marcia Angell’s judgment that the FDA needs further independence from drug companies. Yet her entitlement to this valuable perspective cannot serve as privilege to synthesize new facts and cartoonish institutional portraits.  Her essay profoundly mischaracterizes the FDA’s history and behavior, and hence undermines our common goal of its science‐ and safety‐based reform.   Angell scarcely touches upon Reputation and Power; it is rare to read a book review in which not a single word of the reviewed volume is quoted.  Her claim that I ignore the FDA’s failures is easily refuted. In a book about reputation, I show in the Introduction and 12th chapter of the book that the FDA has lost public trust.  And far from demonstrating “little apparent concern” for the effect of user fees, the book’s reputation‐based account explains that PDUFA embedded industry as an audience as if inside the agency’s head (Chapters 6 and 12).  The book and related research also illustrate how PDUFA’s deadlines distorted agency decisionmaking.  Nor do I ignore “ads aimed directly at consumers,” as I examine these squarely in Chapter 12 (p. 733).  More worrisome, Angell’s essay drips with factual errors and profound historical mischaracterizations.  I provide a longer list at my website [http://people.hmdc.harvard.edu/~dcarpent/angellresponse20100920.pdf].  Several are glaring.     Angell offers a stunningly inept characterization of FDA evidence requirements.  Drug  companies lobbied hard against the placebo trial requirement (they often still do), and the FDA has for decades hardened its approval criteria when the drug is a me‐too therapy (Chapter 7).  The agency increasingly requires an active control trial, and it recently negated the role of non‐inferiority trials in whole drug classes.   A 2007 law already requires what Angell proposes: registration of clinical trials. Contrary to  her claim, the same law also directs $375 million toward postmarket surveillance.     The agency has diligently policed conflict of interest on advisory committees in the last two  years; conflict‐of‐interest waivers have sunk to historic lows, as just 2 percent of them were granted last year.   New FDA leadership, far from being passive, has dismissed agency medical device regulators  and reopened old device approval cases; meanwhile consumer advertisement warning letters to drug companies have more than doubled since 2008.  These errors and mischaracterizations, among many others, demonstrate the risk of converting a book review into a personal soapbox to rehearse talking points the reviewer has been making elsewhere for a decade.  In that time, science, the FDA, and scholarship itself have been passing by Angell’s hollow and specious portraiture.  Marked Version of Letter in Response to Angell Essay in New York Review of Books. Calibri font is the text of the letter to the New York Review of Books; this is displayed in text boxes. Courier font is the I agree with Marcia Angell’s judgment that the FDA needs further independence from drug companies. Yet her entitlement to this necessary perspective cannot serve as privilege to synthesize new facts and cartoonish institutional portraits.  Her essay profoundly mischaracterizes the FDA’s history and behavior, and hence undermines our common goal of its science‐ and safety‐based reform.   Angell scarcely touches upon Reputation and Power; it is rare to read a book review in which not a single word of the reviewed volume is quoted.    Her claim that I ignore the FDA’s failures is easily refuted. In a book about reputation, I show in the Introduction and 12th chapter of the book that the FDA has lost public trust in recent years.  And industry friendliness cannot entirely explain the decline of the FDA’s reputation; it contributed little to the rightly condemned “Plan B decision” in which a morning-after contraceptive was denied over- the-counter access. If anything, the maker of Plan B – Barr Laboratories – had been campaigning for the FDA to have their drug This gets us to a larger issue. How much of the FDA’s demise in recent years was the purported capture through PDUFA (as Angell claims), and how much was the conservative political and policy climate that the U.S. generally experienced? It’s worth remembering that from the early 1980s through 2008, the United States was, but for brief moments whose exception proves the general rule, under conservative and often anti-regulatory leadership. Entire agencies and statutes were gutted and others greatly watered down (ICC, Environmental Protection Agency, repeal of Glass-Steagall in financial regulation); by contrast to these agencies and policy areas, the FDA’s recent history is one of relative regulatory strength. I address this issue directly in chapter 12 (see esp. pp. 731-32). The more important point here is to say that, if one argues that FDA decision making is shaped by industry influence as opposed to a general regulatory conservatism, we must have clear evidentiary standards for making And far from demonstrating “little apparent concern” for the effect of user fees on the FDA, the book’s reputation‐based account  explains (in Chapter 6 and 12) that PDUFA embedded industry as an audience as if inside the agency’s “head” (its cognition and operations).  The book and related research also illustrate how PDUFA distorted the agency’s decisionmaking through deadlines.  The relevant sections of the book are Chapter 6 (pp. 458-461) and Chapter 12 (pp. 732-36). On deadlines, consult Daniel Carpenter, Evan Zucker and Jerry Avorn, “Drug Review Deadlines and Safety Problems,” New England Journal of Medicine, 358 (13) (March 27, 2008) 1354-61. Errata and corrected estimates appear in an exchange with FDA officials: New England Journal of Medicine 359 (1) (July 3, 2008) 95- 98. See also Carpenter, et al., “Deadline Effects in Government Decision Making: A Methodological and Empirical Analysis,” Robert Wood Johnson Foundation Scholars in Health Policy Working Paper #35. Available at http://www.healthpolicyscholars.org/sub- news/working_papers/w45_Carpenter.pdf [accessed September 19, 2010]. More worrisome, Angell’s essay drips with factual errors and deep historical mischaracterizations.  I provide a summary list of these in the following document at my website.  Several are glaring.     Angell offers a stunningly inept characterization of FDA evidence requirements.  Drug companies  lobbied hard against the placebo trial requirement (they still do), and the FDA has long strengthened its criteria (and lengthened its review time) when the drug is plausibly a me‐too therapy (see the statistical evidence in Chapter 7).  The agency increasingly requires an active control trial, and it recently negated the role of non‐inferiority trials in whole drug classes.    On the origins of the placebo requirement and its resistance by industry, see Reputation and Power, 579-80. On the slower approval time for me-too drugs and later entrants in a therapeutic class, see Chapter 7 of Reputation and Power, as well as Daniel Carpenter, et al., “Early Entrant Protection in Approval Regulation: Theory and Evidence from FDA Drug Review,” Journal of Law, Economics and Organization, 26 (2) (Fall 2010) [doi: 10.1093/jleo/ewp002]. A prescient example comes in the case of ropinerole for Parkinson’s (Chapter 7, pp. 505-509), whose labeling was restricted in light of the previous approval of Mirapex. So too with clinical trial standards the FDA has in recent years been raising the bar for therapeutic comparisons. A recent GAO report [http://www.gao.gov/new.items/d10798.pdf] concludes that the agency “has become more conservative in allowing evidence from non- inferiority trials to demonstrate the effectiveness of new drugs.” As an example of this approach, consult the recent guidance document http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInforma tion/Guidances/UCM202140.pdf [accessed September 17, 2010]. And as the reputational perspective taken in Reputation and Power might suggest, drug companies are now submitting fewer NDAs where these trials have been conducted. See also the recent story “The FDA is Cracking Down on Non-Inferiority Trials,” http://www.pharmalot.com/2010/08/the-fda- is-cracking-down-on-non-inferiority-trials/ [accessed September 17, For a recent expression of doubt about non-inferiority trials consider the following summary from Clinical Trials Advisor: “In its continued emphasis on minimizing noninferiority trials in drug development, the FDA is now urging drugmakers to use superiority trials for initial registration of direct-acting antiviral agents for hepatitis C (HCV). Clinical trials for these drugs should be designed to demonstrate superiority to the standard of care regimen of pegylated interferon combined with ribavirin, according to a draft guidance.” See guidance document at: http://www.fdanews.com/ext/files/UCM225333.pdf [accessed September 17, 2010]. “FDA Nixes Noninferiority Trials for Antiviral HCV Candidates,” Clinical Trials Advisor, Sept. 16, 2010 | Vol. http://www.fdanews.com/newsletter/article?articleId=130287&issueId=140 A 2007 law already requires what Angell proposes: registration of clinical trials. Contrary to her claim, the same law also directs tens of millions of user‐fee dollars toward postmarket surveillance.    The FDAAA of 2007 is officially known as U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 or FDAAA). [The basic description here is taken from the federal government’s http://prsinfo.clinicaltrials.gov/fdaaa.html [accessed September 20, 2010].] Title VIII of this law, in Section 801, requires that a "responsible party" (i.e., the sponsor or designated principal investigator) register and report results of certain “applicable At this point, Angell might respond that the database does not yet exist. But no one with a knowledge of federal rulemaking could credibly say that this delay is due to industry pressure; it is a function of the rulemaking process that is all the more elaborate when more than one agency is involved (FDA, NIH and the larger umbrella agency of HHS). In part due to long-standing institutional restrictions under the Administrative Procedures Act of 1946 and in part due to cross-agency cooperation that the database is still being established. The clinical trials registry rules are currently on the (http://www.reginfo.gov/public/do/eAgendaViewRule?pubId=201004&RIN=092 5-AA55 [accessed September 20, 2010]), and university IRBs and sponsored research offices already direct principal investigators to comply with this rule. In addition, companies must now fill out a Certification of Compliance to FDA to accompany Drug, Biological Product, and Device applications or submissions.                                                             1 As the clinicaltrials.gov website defines them, “‘Applicable clinical trials’ generally include interventional studies (with one or more arms) of drugs, biological products, or devices that are subject to FDA regulation, meaning that the trial has one or more sites in the U.S, involves a drug, biologic, or device that is manufactured in the US (or its territories), or is conducted under an investigational new drug application (IND) or investigational device exemption (IDE).” Angell appears to ignore entirely that the 2007 user-fee law adds $375 million in funding of postmarket studies and operations to the agency.2 The General Accounting Office recently issued a report concluding that the FDA has made significant progress in development of a postmarket safety apparatus, though more work remains to be done (see http://www.gao.gov/new.items/d1068.pdf [accessed September 19, 2010]). New FDA leadership, far from being passive, has dismissed its medical device regulators, and consumer advertisement warnings have more than doubled since 2008.    The 15-year head of the medical device center, Daniel Schultz, resigned in August 2009, but it is widely understood that his resignation as director was requested. (See for instance Alicia Mundy, “FDA Medical-Device Regulator Resigns,” Wall Street Journal, August 12, 2009; and the characterization of Hamburg’s intentions at http://www.massdevice.com/news/fda-makes-shurens-appointment-head- medical-devices-division-permanent [accessed September 20, 2010].) In addition, the Commission has begun to open medical device approvals that were, by its own admission, inconsistent with agency procedures and with scientific rigor. One case involved a severe and implicit criticism of congressional members of the Democratic Party. It is significant, then, that Democratic President Obama appointed Hamburg and Sharfstein. (See Alicia Mundy and Jared Favole, “FDA Rips Approval of Medical Device,” Wall Street Journal [http://online.wsj.com/article/SB125382260933538517.html [accessed On advertisements, most would admit that the FDA is ‘outgunned.’ Yet the paucity of officials reviewing physician and consumer advertisements is four decades old, and not something unique to the user-fee era. Angell has no evidence, and there simply is none, that http://www.reuters.com/article/idUSTRE6821PN20100903 [accessed                                                             2 Her claim is that only a “small fraction” of funding goes to postmarket safety, citing the 2002 law; her essay is entirely ignorant of the 2007 law. My estimate of $325 million comes from a presentation by the law firm Wilmer-Hale; see http://www.wilmerhale.com/files/Publication/0fe9f6cf-caba-4af2-a33c-85cc538cd4b2/Presentation/PublicationAttachment/4686acd6-a550-4753-97e9-8c782e9bb5ad/Lassman_FDAAA_Audioconference_Series_10_4_07.pdf [accessed September 19, 2010].   Angell would have readers believe that the FDA is dragging its feet on the Avandia case,3 but she has nothing in the way of solid evidence for this claim. First, the advisory committee vote was split in numerous directions, and some of the strongest voices in favor of keeping Avandia on the market in a limited way were some of the least- conflicted members (e.g., Sanjay Kaul of UCLA Medical Center, who was particularly outspoken about the lack of evidence in favor of another drug, prasugrel, which an advisory committee discussed in February 2009).4 Second, as I discussed, the Office of New Drugs has some personnel who have aggressively made a scientific case against Avandia and the recent clinical trials that the company purports to demonstrate its safety. If the Office of New Drugs were constantly resisting the Office of Drug Safety, as Angell implies, then she would have a very difficult time explaining Thomas Marciniak’s memo on the http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMater ials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218493.
pdf [accessed September 20, 2010]]. It was not a drug safety officer but an Office of New Drugs member and new drug reviewer who pointed to problems in Glaxo SmithKline’s postmarket randomized controlled trial On the suppression of information, I agree that these revelations are troubling, and I think Gardiner Harris of the New York Times has done immense public service by bringing them to light. But the idea that the stories themselves serve as a sufficient rationale for the immediate market withdrawal of the drug is untenable. In a system dominated by the rule of law, any such claims must be investigated by statutorily authorized prosecutors. (I understand that the Department of Justice is investigating them now.) Moreover, Angell’s claim reflects a hollow understanding of modern pharmaceutical regulation (not to mention administrative law). From the standpoint of law, any allegations of law-breaking must be proven, and again from the standpoint of law, the FDA must consider Avandia not in the light of                                                             3 Angell, in the second paragraph of her essay: “Even after revelations that the drug’s maker…suppressed indications of problems and biased its research in Avandia’s favor, the FDA remained reluctant to pull the drug.” 4 It is worth noting that Kaul was inexplicably removed from this panel, raising questions about the Office of New Drugs’ power over the committee and its decision making. Yet these are issues that I discuss consistently in my book – how CDER Directors and the Office of New Drugs has greater power over the membership, agenda and meeting format of advisory committees than do possible drug skeptics in the postmarket safety offices (R&P, Chapter 9, 622).   media reports about the behavior of its company, but in light of its The agency has diligently policed conflict of interest on advisory committees in the last two years; conflict‐of‐interest waivers have sunk to historic lows, just 2 percent of them were granted last year.    The data here are quite clear. See slide 13 at http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM192786.pd f [accessed September 19, 2010]. Note also the slowdown in conflict- of-interest waivers granted, from 36% in 2006 to 2% [for appreciably more advisory committee meetings] in 2009. An exemplary case occurs in the very individual whom Angell cites in the Avandia case: Clifford Rosen, who chaired the recent rosiglitazone advisory panel, and who penned the New England Journal of Medicine perspective quoted in her essay. In that New England Journal piece, he actually called for removing the drug from the market OR an extremely tough risk Evaluation and Mitigation Strategy (REMS) could allow continued sale. Ultimately, Stephen Nissen of the Cleveland Clinic was right, in claiming after the July Avandia panel meeting, that Avandia is done. Either it will be withdrawn or its use will be so heavily restricted through a REMS that its market with wither. In other words, Clifford Rosen is evidence against Angell’s simplistic portrait of FDA advisory committees, not for it. In addition, note that in the area of diet pills, FDA advisory committees have in recent years and months issued starkly negative judgments about efficacy and safety. Two diet drugs recently rejected http://www.pharmalot.com/2010/09/fda-panel-rejects-arena-pharmas-diet- http://www.pharmalot.com/2010/07/fat-chance-fda-panel-rejects-the- These errors and mischaracterizations, among many others, demonstrate the risk of converting a book review into a personal soapbox to rehearse talking points the reviewer has been making elsewhere for a decade.  In that time, science, the FDA, and scholarship itself have passed Marcia Angell by.  This concludes material pertaining to my official letter to the New York Review of Books. In looking back, I suspect Angell was caught off guard (or annoyed) by my suggestion early on in the book that her own volume – The Truth About the Drug Companies – was too simplistic At least for the initial PDUFA law, it is incorrect to say that it was the product of industry lobbyists alone. Industry lobbyists resisted user fees for years in favor of tighter deadlines or wholesale deregulation (weakening of the efficacy requirement). Only when disease advocates joined companies in lobbying for them was Commissioner David Kessler able to broker a coalition for their use (Reputation and Power, Chapter 6, p. 460). The final act was co- sponsored by Edward Kennedy (hardly in the pocket of drug companies in the early 1990s) and Orrin Hatch, and it passed the Senate unanimously. In other words, PDUFA has problems, but they are largely consequences that were not intended by the original authors (including It is true that industry lobbyists have been empowered by the PDUFA law, as they sit in on the negotiation of the draft renewal acts every five years. Yet this is something that I discuss explicitly in the book, in chapters that Angell reports that she read. Generic drugs. Again the absence of historical understanding in Angell’s review unfortunate. FDA regulations and decisions have not so much impeded the generic drugs market as they have constituted that market whole. In a recent paper with University of Minnesota historian Dominique Tobbell, I provide a review of the FDA’s rulemaking and methodological work in bioequivalence. I also discuss bioequivalence standards at various points in the book; suffice it to say that we would not even have a vibrant generic drugs industry if not for this forceful, progressive and science-based rulemaking by the It is true that many observers see need for quicker generic drug approval, but it is also true that historically, the agency is relatively quick with these decisions. From 1979 to the present, the FDA has on average reviewed generic drugs in three months’ less time than for non-generic drug reviews. From 1989 onward, the difference is eight months when outlier cases of reviews lasting longer than six years are excluded. The statutory timeline for these cases is 180 days; the FDA often goes over these deadlines, but exceeds the deadlines at least as often for non-generic reviews. Angell is also wrong about the failure to enforce off-label promotion – there are numerous cases prosecuted in recent years, and these are referred to the Department of Justice. It is the Department of Justice, not the FDA, that alone can bring criminal or civil charges in these cases. Her claim that there is “little interference from CDER” in these cases simply misses the legal structure of the enforcement; CDER and other whistleblowers refer these cases to the proper law enforcement agency in the federal government. Staffing for non-review functions. Angell asks “How can a staff of 83 possibly ensure that thousands of foreign manufacturing plants under its purview follow good manufacturing practices?” I certainly agree that non-review, and I have written elsewhere that PDUFA is partially to blame for this. Yet again, Angell’s portrait is misleading, in part because even in the United States the FDA employs regional inspectors (not employees based in Washington or Maryland) to examine both domestically manufactured and imported drugs. And it is worth pointing out that the FDA itself created good manufacturing practices, which are routinely applied by foreign governments to their Speed of NDA review. By any reasonable definition of “a few months,” the FDA almost never reviews drugs so quickly, and has not reviewed drugs in “a few months” with any regularity since the early 1950s. See Chapters 3 and 7 of Reputation and Power, and the data posted at http://people.hmdc.harvard.edu/~dcarpent/fdadatabasic.csv [accessed September 20, 2010]. Reviews since this database were completed have been even slower. I am aware that some more procedural stringency may have public health benefits, in light of recent problems and in light of the difficulties created for the FDA by user- On surrogate endpoints, Angell’s discussion is also quite misleading. It is true that statin drugs have been approved on the basis of cholesterol reduction, but that is because they were
submitted for the primary indication of cholesterol reduction (or, in
other cases, reduction of triglyceride levels or reduction of blood pressure). In other words, the very definition of the disease is in terms of the non-clinical measure; it is not generally the case that drugs are being approved explicitly for prevention of heart-attack, stroke, atherosclerosis or clinical cardiac events based upon surrogate measures like cholesterol reduction. First, this pattern of new etiologies of disease emerging, partly at the behest of drug companies, is hardly new. As my colleague Jeremy Greene argues in his insightful book Prescribing by Numbers (Johns Hopkins, 2008), the creation of new diseases by pharmaceutical companies has been with us for a long time. And the “surrogate endpoints” such as non-clinical outcomes have been used for drugs for decades before the user-fee law, as in the case of the FDA’s approval of beta-blockers in the 1970s. (I tend to agree, for what it is worth, that the FDA’s notorious delay of beta-blockers in the 1970s has been vastly overstated by libertarian critics of the FDA. This is especially so in light of recent evidence that anti-diuretics perform Generally, when statin drugs are approved by the FDA for the reduction of cardiac risk or death, CDER uses not the surrogate endpoint of lower cholesterol but rather heart attacks, strokes and cardiovascular deaths as the pivotal endpoint. In the following section I give an The relevant statins are Lipitor (atorvastatin), Lescol (fluvastatin), Mevacor (lovastatin), Pravachol (pravastatin), Zocor (simvastatin), Crestor (rosuvastatin) I take these drugs in turn. In every case, Angell’s characterization of the relationship between surrogate endpoints and approval is deeply misleading. Pravachol (pravastatin). Here the direct approval for reduction of
atherosclerotic risk and stroke prevention was not given until the
completion of two critical studies:
(1) The Cholesterol and Recurrent Events (CARE) trial at Brigham and Women’s Hospital in Boston, Massachusetts. (2) the Pravastatin Primary Prevention Study (or the so-called West of Scotland Coronary Prevention Study (WOS)).5 Lescol (fluvastatin). Lescol was not given an indication for reduction
of cardiovascular risk until clinical outcomes were used in the Lescol
intervention Prevention Study; consult the review for this indication
at
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/020261_S033_LES
COL_CAPS_AP.pdf [p. 13 of document, accessed September 19, 2010].
Mevacor (lovastatin). Mevacor was also approved initially for
reduction of cholesterol. But its approval for reduction of
cardiovascular risk did not occur until it demonstrated clinical
outcomes. This occurred in the Air Force/Texas Coronary
Atherosclerosis Prevention Study (AFCAPS/TexCAPS). See
http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/19643s075lbl.
pdf [accessed September 19, 2010].
 Zocor (simvastatin)  Crestor (rosuvastatin)  Caduet (atorvastatin/amlopZZZ). This drug was submitted for treatment of hypertension. http://www.centerwatch.com/drug-information/fda-approvals/drug-details.aspx?DrugID=847 While lower cholesterol was measured in these trials (since it is the postulated mechanism for reduction cardiac event risk), the pivotal approval decision for approval for clinical outcomes was made on the basis of observed clinical outcomes in the study. It is, finally, worth stating that many clinicians, observers and scholars have begun to reassess the benefit-risk profile of statins and others have called for more postmarket safety evaluation of these widely used drugs. A particularly judicious call for more research into the adverse events associated with statins comes in a 2007 letter to the FDA from the Consumers’ Union; consult http://www.consumersunion.org/FDA%20Statins%20Letter%2011-16-07.pdf                                                              5 According to the website pslgroup.com, when the FDA relied upon this trial in its 1998 approval of Pravachol for stroke prevention, it was “the first time that the FDA has cleared a drug such as Pravachol, which is a member of the HMG-CoA reductase inhibitor class of drugs, for use in reducing the risk of stroke. In addition, Pravachol is the first drug of its kind to receive FDA clearance for use in reducing the risk of recurrent heart attack and death from heart disease in patients with normal cholesterol levels.” (http://www.pslgroup.com/dg/6842e.htm [accessed September 20, 2010]).

Source: http://people.hmdc.harvard.edu/~dcarpent/angellresponse20100920-original.pdf