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\li0\ri0\sl-20\slmult0\nowidctlpar\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 { \par }}{\*\aftnsepc \pard\plain \ql \li0\ri0\nowidctlpar\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 { }{ \par }}{\*\aftncn \pard\plain \ql \li0\ri0\nowidctlpar\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 { }{ \par }}\sectd \pgnrestart\linex0\headery1440\footery1440\sectdefaultcl {\*\pnseclvl1\pnucrm\pnstart1 {\pntxta .}}{\*\pnseclvl2\pnucltr\pnstart1 {\pntxta .}}{\*\pnseclvl3\pndec\pnstart1 {\pntxta .}}{\*\pnseclvl4\pnlcltr\pnstart1 {\pntxta .}}{\*\pnseclvl5 \pndec\pnstart1 {\pntxtb (}{\pntxta )}}{\*\pnseclvl6\pnlcltr\pnstart1 {\pntxtb (}{\pntxta )}}{\*\pnseclvl7\pnlcrm\pnstart1 {\pntxta )}}{\*\pnseclvl8\pnlcltr\pnstart1 {\pntxta )}}{\*\pnseclvl9\pnlcrm\pnstart1\pnindent720\pnhang{\pntxtb (}{\pntxta )}} \pard\plain \s30\ql \li0\ri0\nowidctlpar\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\v\expnd0\expndtw-2 \par }\pard\plain \ql \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx360\tx1080\tx1800\tx2520\tx3240\tx3960\tx4680\tx5400\tx6120\tx6840\tx7200\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 \par \par \par }\pard \qc \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx360\tx1080\tx1800\tx2520\tx3240\tx3960\tx4680\tx5400\tx6120\tx6840\tx7200\hyphpar0\faauto\rin0\lin0\itap0 {\b\f0\fs24 THE REGULATION OF DRUG MANUFACTURING CHANGES:}{\f0\fs24 \par }\pard\plain \s1\qc \li0\ri0\sl240\slmult0\keepn\nowidctlpar\tx0\tx360\tx1080\tx1800\tx2520\tx3240\tx3960\tx4680\tx5400\tx6120\tx6840\tx7200\hyphpar0\faauto\outlinelevel0\rin0\lin0\itap0 \fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 { PAST, PRESENT, AND FOREIGN \par }\pard\plain \qc \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx360\tx1080\tx1800\tx2520\tx3240\tx3960\tx4680\tx5400\tx6120\tx6840\tx7200\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs24 \par \par \par \par \par \par by Peter J. Schildkraut \par for Peter Barton Hutt \par Food & Drug Law}{\fs24 }{\field{\*\fldinst {\fs24 PRIVATE }{\fs24 {\*\datafield 0c0070686f656e697800010000000000}}}{\fldrslt }}{\fs24 \par }{\f0\fs24 January 24, 1997}{\fs24 \page \page \par }\pard \ql \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx360\tx1080\tx1800\tx2520\tx3240\tx3960\tx4680\tx5400\tx6120\tx6840\tx7200\hyphpar0\faauto\rin0\lin0\itap0 {\fs24 \par }{\b\f0\fs24 INTRODUCTION}{\f0\fs24 \par \par \par }\pard \qj \fi-540\li540\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin540\itap0 {\f0\fs24\expnd0\expndtw-3 \tab \tab The manufacturing processes a nd facilities used to produce a new drug or biological product are under change throughout the investigation of the product and after marketing approval is obtained from the FDA. Innovations are sought to reduce impurities, increase yield, reduce the com p lexity and time required for manufacture, eliminate equipment, automate procedures, increase stability, and otherwise to improve the drug and reduce its cost. The benefits of these innovations are passed on to the consumer in the form of improved product s and lower prices.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx0\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2 \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2 S. R}{\scaps\f0\expnd0\expndtw-2 ep. No.}{ \f0\expnd0\expndtw-2 104-284, at 39 (1996) (accompanying the Food and Drug Administration Performance and Accountability Act of 1995, S. 1477, 104th Cong. (1996) (as reported by the Senate Committee on Labor and Human Resources)). \par }}}{\fs24\expnd0\expndtw-3 \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 \par With these words, the Senate Committee on Labor and Human Resources introduced its efforts to reform the Food and Drug Administration\rquote s (FDA) treatment of proposed changes in the manufacturing of pharmaceuticals. The committee ech oed the industry\rquote s complaints that the FDA undertakes (and forces companies to await the outcomes of) more thorough reviews of such proposals than are necessary to preserve drugs\rquote safety and efficacy.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super }{\i\f0\expnd0\expndtw-2\super See id.}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par According to manufacturers and the committee, these requirements and delays have some unwelcome effects on public health, consumers, industry, and the U.S. economy. First, since foreign countries impose lesser regulatory burdens, \'93 many companies have established manufacturing facilities abroad, where they can use a modern process to supply a drug to the rest of the world long before they can use the same process to supply the United States.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Unfortunately, it is extremely difficult to come by data to back up this claim. For political reasons, manufactu rers do not publicize their moves to offshore production, and the industry association (the Pharmaceutical Research and Manufacturers of America or PhRMA) does not survey its members on the subject.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\i\f0\fs20\expnd0\expndtw-2\super See }{\f0\fs20\expnd0\expndtw-2\super Telephone Interview with Matthew B. Van Hook, Assistant General Counsel, PhRMA (Jan. 10, 1997) [hereinafter Van Hook Interview]. Mr. Van Hook suggested a comparing the age of manufacturing plant and equipment in the United States with other cou ntries as a proxy, but I was unable to locate such data in the time frame I had to write this paper.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Second, the cost and length of the regulatory approval process induces some companies not to attempt to introduce \'93important drug manufacturing improvements.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super S. R}{\scaps\f0\fs20\expnd0\expndtw-2\super ep. No.}{\f0\fs20\expnd0\expndtw-2\super 104-284, at 39}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Third, drug prices remain \'93unnecessarily high\'94 whether or not manufacturers institute changes either because they retain the older, more expensive tec hnology or because they invest resources in unwarranted regulatory reviews.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par Although FDA reform legislation died in the 104th Congress, congressional leaders will continue to push the proposals in the 105th Congress.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See}{\f0\fs20\expnd0\expndtw-2\super John Schwartz, }{\i\f0\fs20\expnd0\expndtw-2\super In Swan Song, Kessler Croons of FDA Progress}{\f0\fs20\expnd0\expndtw-2\super , }{ \scaps\f0\fs20\expnd0\expndtw-2\super Wash. Post}{\f0\fs20\expnd0\expndtw-2\super , Dec. 11, 1996, at A23, }{\i\f0\fs20\expnd0\expndtw-2\super available in }{\f0\fs20\expnd0\expndtw-2\super LEXIS, News Library, WPost File; John Schwartz, }{ \i\f0\fs20\expnd0\expndtw-2\super With Leadership in Transition, FDA to Face Many Challenges in New Congress}{\f0\fs20\expnd0\expndtw-2\super , }{\scaps\f0\fs20\expnd0\expndtw-2\super Wash. Post}{\f0\fs20\expnd0\expndtw-2\super , Dec. 1, 1996, at A30, }{ \i\f0\fs20\expnd0\expndtw-2\super available in }{\f0\fs20\expnd0\expndtw-2\super LEXIS, News Library, WPost File.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 This paper examines the history of FDA regulation of manufacturing supplements for drugs,}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Although closely related and frequently treated ide ntically in current reform proposals, the regulation of manufacturing supplements for biological products has a separate history and is, thus, outside the scope of this paper.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 summarizes the current equivalent regulations of the European Union (EU), and concludes by discussing some current proposals for reforming the U.S. rules. \par \par }\pard \qc \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\b\fs24 THE HISTORY OF FDA REGULATION OF MANUFACTURING SUPPLEMENTS}{\fs24 \par }\pard \ql \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24 \par \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 Over the last three and one-half decades, the Food and Drug Administration has gradually loosened its controls on manufacturing changes to approved new drug applications (NDAs). The relaxations in the 1960s appear to have been sim ple, common-sense reactions to presumably unanticipated and }{\i\fs24\expnd0\expndtw-3 completely}{\fs24\expnd0\expndtw-3 indefensible rigidities in the regulations, and I would guess that they were noncontroversial.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super I attempted to confirm this hunch during a conversation with William Goodrich, the FDA\rquote s Chief Counsel during this period, but was unable to elicit a direct answer. }{\i\f0\expnd0\expndtw-2\super See}{\f0\expnd0\expndtw-2\super Telephone Interview with William Goodrich, former Chief Counsel, FDA (Jan. 22, 1997) [hereinafter Goodrich Interview].}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 However, the history since the 1970s has reflected the ebb and flow of the power of the agency\rquote s chemists. \par The chemists\rquote institutional culture has reflected an extreme risk aversion in approving drugs and changes to approved drugs.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See }{\f0\fs20\expnd0\expndtw-2\super Telephone Interview with William Vodra, Partner, Arnold & Porter (Jan. 9, 1997) [hereinafter Vodra Interview].}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 As the McMahon Commission noted in 1982: \par \par }\pard \qj \fi-540\li540\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin540\itap0 {\fs24\expnd0\expndtw-3 \tab Difficulties in satisfying NDA requirements concerning chemistr y and manufacturing controls have significantly contributed to delays in the approval of new drugs. [A 1980 General Accounting Office report] concluded that the FDA\rquote s review of the chemistry portion of the NDA takes longer than do the pharmacological and medical reviews. Subsequently, the FDA reported that the majority of the deficiencies in NDAs are related to chemistry and manufacturing.}{ \f0\fs24\expnd0\expndtw-3 }{\f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt\f3\fs24}}}{\f0\fs24\expnd0\expndtw-3 [T]he Commission believes that [the] significance [of the chemistry requirements] to the public health is rarely of the same magnitude as the kinds of issues regarding clinical evidence of safety and effectiveness discussed elsewhere in this report. The chemistry problems stem from a different set of reasons; they often appear overly technical and trivial.}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super }{\scaps\f0\expnd0\expndtw-2\super Subcommittee on Natural Resources, Agriculture Research and Environment & Subcommittee on Investigations and Oversight, 97th Cong., Commission on the Federal Drug Approval Process: Final Report}{\f0\expnd0\expndtw-2\super 76-77 (Comm. Print 1982) [hereinafter }{\scaps\f0\expnd0\expndtw-2\super McMahon Commission Report}{\f0\expnd0\expndtw-2\super ].}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 This cul tural conservatism stems from the criticism the FDA received after one drug disaster in the early 1940s and another in the early 1960s.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super }{\i\f0\expnd0\expndtw-2\super See }{\f0\expnd0\expndtw-2\super Vodra Interview, }{\i\f0\expnd0\expndtw-2\super supra }{\f0\expnd0\expndtw-2\super note 10 (based on Mr. Vodra\rquote s recollection of a conversation with William Goodrich, former Chief Counsel of the FDA). Although Mr. Vodra could not recall the name of the 1940s drug, he explained that the 1960s problem involved a generic copy of Smith, Kline & French\rquote s chlorpromazine. Mr. Goodrich no longer remembers the incidents. }{\i\f0\expnd0\expndtw-2\super See}{ \f0\expnd0\expndtw-2\super Goodrich Interview, }{\i\f0\expnd0\expndtw-2\super supra}{\f0\expnd0\expndtw-2\super note 9.}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 In both cases, manufacturers created generic drugs through different modes of synthesis from the pioneers, and these new modes of synthesis unexpectedly left behind harmful residues.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See}{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super id.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 As a result, agency chemists have sought to review thoroughly all potential chemical changes in drugs.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Whatever one thinks of the social value of this caution, it reflects the institutional incentives facing the FDA\rquote s employees. The American public and the Congress have tended to perceive, and thus react, much more strongly to erroneous (in hindsight) approvals of me dicines that lead to disasters than to delays in approvals that postpone or even prevent new therapies. The Congress has gone so far as to call FDA line employees at a GS-9 level to testify (i.e., be harangued by Representatives or Senators) about their mistakes. }{\i\f0\fs20\expnd0\expndtw-2\super See}{\f0\fs20\expnd0\expndtw-2\super Telephone Interview with Jerome Halperin, Executive Director, The United States Pharmacopeial Convention, Inc., and former Deputy Director, FDA Center for Drug Evaluation and Research (Jan. 15, 1997) [hereinafter Halperin Interview].}{ \f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par \par Historically, FDA managers have had great difficulty in limiting these reviews because, ultimately, they have had to depend upon the chemists\rquote expertise to determine what information FDA needed to judge the safety and efficacy of a drug. As the McMahon Commission noted, \'93The senior line managers usually have backgrounds in medicine o r biology and may not fully understand chemistry problems. As a result, requests by chemists for more information, additional specifications, or special analyses cannot routinely be reviewed by these managers for reasonableness or justification.\'94}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super }{\scaps\f0\expnd0\expndtw-2\super McMahon Commission Report}{ \f0\expnd0\expndtw-2\super , }{\i\f0\expnd0\expndtw-2\super supra}{\f0\expnd0\expndtw-2\super note 11 at 77.}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par Over the last few years, however, two changes have altered this entrenched culture of risk aversion. First, Dr. Roger Williams, a Deputy Director of the FDA\rquote s Center for Drug Evaluation and Research (CDER), has had the chemistry background to supervise the Center\rquote s chemists meaningfully.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See }{\f0\fs20\expnd0\expndtw-2\super Halperin Interview, }{\i\f0\fs20\expnd0\expndtw-2\super supra}{\f0\fs20\expnd0\expndtw-2\super note 14.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Under his leadership, the agency has liberalized the rules governing manufacturing changes through the Scale-Up and Postapproval Changes (SUPAC) guidance described below.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Immediate Release Solid Oral Dosage Forms; Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing; In Vivo Bioequivale nce Documentation; Guidance, 60 Fed. Reg. 61638 (1995) [hereinafter SUPAC Guidance]; }{\i\f0\fs20\expnd0\expndtw-2\super see }{\f0\fs20\expnd0\expndtw-2\super Jill Wechsler, }{\i\f0\fs20\expnd0\expndtw-2\super Washington Report: Tug-of-War with FDA}{ \f0\fs20\expnd0\expndtw-2\super , }{\scaps\f0\fs20\expnd0\expndtw-2\super Pharmaceutical Executive}{\f0\fs20\expnd0\expndtw-2\super , May 1996, at 18, 20, 22 (describing the leadership of Williams).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Second, a new generation of chemists with a less conservative attitude towards risk has entered the agency.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Halperin Interview, }{\i\f0\fs20\expnd0\expndtw-2\super supra}{\f0\fs20\expnd0\expndtw-2\super note 14.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Together, these changes have created an environment in which the industry can more easily make manufacturing changes that have no significant risk of affecting safety or efficacy. \par }\pard \qc \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\b\fs24\ul 1963: The Initial Regulation}{\fs24 \par }\pard \ql \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24 \par \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 Following the enactment of the Drug Amendments of 1962,}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super Pub. L. No. 87-781, 76 Stat. 780 (amending the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. \'a7\~301 (1994)).}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 the Food and Drug Administration substantially expanded its regulations enforcing the Federal Food, Drug, and Cosmetic Act in 1963.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0 \nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super 28 Fed. Reg. 6375 (1963).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 This massive rewrite included a new section governing changes to approved NDAs.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 6381 (codified at 21 C.F.R. \'a7 130.9, recodified as amended at 21 C.F.R. \'a7 314.8 by 39 Fed. Reg. 11680 (1974), recodified as amended at 21 C.F.R. \'a7 314.70 by 50 Fed. Reg. 7452, 7498 (1985)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Section 130.9(a) provided that \'93[a]fter an application is approved, a supplemental application may propose changes\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0 \nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id. }{\f0\fs20\expnd0\expndtw-2\super (codified at 21 C.F.R. \'a7 130.9(a)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 and stipulated that a supplement \par \par }\pard \qj \fi-540\li540\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin540\itap0 {\fs24\expnd0\expndtw-3 \tab should be submitted for any change beyond the variations provided f or in the application (including changes in the scale of production, such as from pilot-plant to production batch), that may alter the conditions of use, the labeling, the safety, effectiveness, identity, strength, quality, or purity of the drug, or the a dequacy of the manufacturing methods, facilities, or controls to preserve them.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super }{\i\f0\expnd0\expndtw-2\super Id.}{ \f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 \par Subsection (c) gave manufacturers a huge incentive to wait for FDA approval of such supplements before implementing any changes; this provision permitted the agency to suspend or withdraw the approval of an NDA if the manufacturer marketed a \'93 changed\'94 drug prior to FDA approval of the supplement.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super }{\i\f0\expnd0\expndtw-2\super Id.}{\f0\expnd0\expndtw-2\super (codified at 21 C.F.R. \'a7 130.9(c)).}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 However, the regulation did offer a safe harbor for \'93changes}{\f0\fs24\expnd0\expndtw-3 }{\f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt\f3\fs24}}}{\f0\fs24\expnd0\expndtw-3 that are not significant from the standpoint of safety or effectiveness.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super (codified at 21 C.F.R. \'a7 130.9(d)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 But, the value of this safe harbor to manufacturers was limited by a further provision that the agency would determine \'93whether the approval of a supplemental application is required for such change or changes.\'94}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Thus, a manufacturer that believed its proposal was insignificant and wished to avoid filing a supplement still had to \'93submit}{\f0\fs24\expnd0\expndtw-3 }{\f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt\f3\fs24}}}{\f0\fs24\expnd0\expndtw-3 , in writing, full details of any proposed change or changes\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 and wait for the FDA to concur or to request a formal supplement. In effect, manufacturers lacked the authority to implement a manufacturing change without some form of agency preclearance. \par }\pard \qc \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\b\fs24\ul 1965: The Erosion Begins}{\fs24 \par }\pard \ql \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24 \par \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 The Food and Drug Administration quickly realized that these regulations were too restrictive. In 1965 the agency amended the s afe harbor provisions to enable manufacturers to effect certain improvements in safety and effectiveness without any form of premarketing approval.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super 30 Fed. Reg. 993, 993-94 (1965) (amending 21 C.F.R. \'a7 130.9).}{ \f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Among the three listed changes that \'93should be placed into effect at the earliest possible time\'94 were \par \par }\pard \qj \fi-540\li540\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin540\itap0 {\fs24\expnd0\expndtw-3 \tab [c ]hanges in the methods, facilities, or controls used for the manufacture, processing, packing, or holding of the drug (other than utilization of establishments not covered by the approval that is in effect) that give }{\i\fs24\expnd0\expndtw-3 increased assurance}{\fs24\expnd0\expndtw-3 that the drug will have the characteristics of identity, strength, quality, and purity which it purports or is represented to possess.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super }{\i\f0\expnd0\expndtw-2\super Id.}{ \f0\expnd0\expndtw-2\super (amending 21 C.F.R. \'a7 130.9(d)(3)) (emphasis added).}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 Under this revision, manufacturers had to submit a supplemental application for such changes,}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super I will refer to such supplements as \'93changes-being-effected supplements. \'94}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 but the FDA committed itself \'93to take no action against a drug or applicant solely because\'94 the manufacturer has implemented the changes prior to FDA approval.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 994 (amending 21 C.F.R. \'a7 130.9(e)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par }\pard \qc \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\b\fs24\ul 1968: The FDA Relaxes Further}{\fs24 \par }\pard \ql \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24 \par \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 Three years later, the agency first permitted manufacturers to notify it of manufacturing changes that are not expected to have a material negative effect on safety or effectiveness subsequent to the changes\rquote implementation.}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super 33 Fed. Reg. 9954, 9954-55 (1968) (amending 21 C.F.R. \'a7 130.9).}{ \f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Instead of filing a supplement, the companies could merely notice certain specified changes in the next periodic report on the drug.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See id. }{\f0\fs20\expnd0\expndtw-2\super at 9955. Currently, such reports are required annually. }{\i\f0\fs20\expnd0\expndtw-2\super See }{\f0\fs20\expnd0\expndtw-2\super 21 C.F.R. \'a7 314.81(b)(2) (1996).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 The specified nonmaterial changes included \'93A different container size for solid oral dosage forms where container and closure are of the same materials as those provided for in the approved application\'94;}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super 33 Fed. Reg. at 9955 (amending 21 C.F.R. \'a7 130.9(a)(5)(i)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 a \'93[c]hange in personnel not involving new facilities\'94;}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super (amending 21 C.F.R. \'a7 130.9(a)(5)(ii)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \'93[c]hange in equipment that does not alter the method of manufacture of a new drug substance or dosage form of a new drug\'94;}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0 \nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super (amending 21 C.F.R. \'a7 130.9(a)(5)(iii)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 a \'93[c]hange from one commercial batch size to another without any change in manufacturing procedure\'94;}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super (amending 21 C.F.R. \'a7 130.9(a)(5)(iv)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 a \'93[c]hange to [a] more stringent specification without altering the method described in the approved application\'94;}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0 \nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super (amending 21 C.F.R. \'a7 130.9(a)(5)(v)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 the \'93[i]nclusion of additional specifications and methods without deletion of those described in the approved application\'94;}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0 \nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super (amending 21 C.F.R. \'a7 130.9(a)(5)(vi)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 and the \'93[a]lteration of specifications or methods for inactive ingredients to bring them into compliance with new or revised specifications or methods in an official compendium.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super (amending 21 C.F.R. \'a7 130.9(a)(5)(vii)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par \par The 1968 amendments did reduce the reporting requirements facing pharmaceutical companies. Neverthele ss, the exceptions were quite narrow, so the regulations continued to force manufacturers to file supplements and incur the costs of awaiting agency approval in order to incorporate improved production technologies. \par }\pard \ql \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24 \par }\pard \qc \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\b\fs24\ul 1985: The Mid-80s Rewrite of the IND}{\cs18\b\fs24\ul\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx0\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\b\f0\fs18\ul\expnd0\expndtw-2 \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx0\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\b\f0\ul\expnd0\expndtw-2 Investigational new drug. }{\b\i\f0\ul\expnd0\expndtw-2 See}{ \b\f0\ul\expnd0\expndtw-2 }{\b\i\f0\ul\expnd0\expndtw-2 generally }{\b\f0\ul\expnd0\expndtw-2 21 C.F.R. pt. 312 (1996).}{\f0\expnd0\expndtw-2 \par }}}{\b\fs24\ul /NDA Regulations \par }{\fs24 \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 Over the next seventeen years a public perception gradually grew that the Food and Drug Administration\rquote s approval processes for investigational new drug applications and new drug applications (including supplements) were too rigorous. As the FDA described this history in 1982: \par }\pard \ql \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24 \par \par }\pard \qj \fi-540\li540\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin540\itap0 {\fs24\expnd0\expndtw-3 \tab This country\rquote s drug approval process has been the subject of extensive debate over the past decade. Critics contend that FDA\rquote s regulations and testing requirements are excessive, thereby stifling innovation a nd depriving the American public of beneficial new therapies. They further contend that FDA\rquote s review of new drug applications}{\f0\fs24\expnd0\expndtw-3 }{\f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt \f3\fs24}}}{\f0\fs24\expnd0\expndtw-3 takes much too long and that, as a result, new therapies are often available in foreign countries before they are available in this country.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx0\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2 \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2 New Drug and Antibiotic Regulations, 47 Fed. Reg. 46622, 46622 (1982) (to be codified at 21 C.F.R. pt. 314) (proposed Oct. 19, 1982) [hereinafter 1982 Proposal]. Although this discussi on refers to the availability of new drugs in this country, it applies similarly to the use of newer manufacturing technologies that improve quality and reduce cost. \par }}}{\fs24\expnd0\expndtw-3 \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 Leaders of the House Committee on Science and Technology like James H. Scheuer (D - N.Y.); Albert Gore, Jr. (D - Tenn.); and George E. Brown, Jr. (D - Cal.) became concerned that the agency\rquote s attitude towards risk was unbalanced. In essence , they feared that the FDA was so focused on maximizing its certainty of the safety and efficacy of approved drugs that it ignored the public health (and other) risks associated with delaying the approval of new drugs or alterations to existing ones.}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super }{\i\f0\expnd0\expndtw-2\super See }{\scaps\f0\expnd0\expndtw-2\super McMahon Commission Report}{\f0\expnd0\expndtw-2\super , }{\i\f0\expnd0\expndtw-2\super supra}{\f0\expnd0\expndtw-2\super note 11, at vi-viii.}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Although it couched its language more diplomatically, the McMahon Commission strongly implied that \'93[t]he present NDA requirements for information about chemistry and manufacturing controls [were] excessive.\'94}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 77. The bracketed \'93were\'94 replaces the actual \'93may be\'94 in order to convey the tone of the discussion more accurately.}{ \f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 In fact, the President\rquote s Task Force on Regulatory Relief, chaired by then-Vice President George Bush, named the drug approval process as one of its top twenty priorities for reform.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super 1982 Proposal, 47 Fed. Reg. at 46622.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par \par In the face of this pressure, the chemists had to back down. During the course of the FDA\rquote s own review of the IND and NDA procedures, the Pharmaceutical Manufacturers Association and Parke-Davis petitioned the agency \'93 to expand the kinds of changes an applicant can make under an approved application and place in effect before receiving agency approval of the change.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0 \nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super }{\i\f0\expnd0\expndtw-2\super Id. }{\f0\expnd0\expndtw-2\super at 46634-35. }{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 When the FDA proposed its NDA rewrite in October 1982, it included a substantial amendment to the regulations for supplemental NDAs,}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See id.}{\f0\fs20\expnd0\expndtw-2\super at 46634-36, 46650-51 (to be codified at 21 C.F.R. \'a7 314.70).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 which was largely retained when the agency promulgated the final rule in February 1985.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See }{\f0\fs20\expnd0\expndtw-2\super New Drug and Antibiotic Regulations 50 Fed. Reg. 7452, 7466-70, 7498-99 (1985) (codified at 21 C.F.R. \'a7 314.70) [hereinafter 1985 Rewrite].}{ \f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par Although the 1985 rewrite preserved the prior three-tier system (filing a supplement for premarketing approval, filing a changes being effected supplement, and annual reporting),}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 7498 (codified at 21 C.F.R. \'a7 314.70(a)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 it established a new baseline for reporting changes to approved NDAs. Instead of providing that a chan ge would require premarketing approval of a supplement unless it fell within one of the listed exceptions, the regulation made }{\i\fs24\expnd0\expndtw-3 post hoc}{\fs24\expnd0\expndtw-3 annual reporting the default.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 7499 (codified at 21 C.F.R. \'a7 314.70(d)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Changes that still required premarketing approval included \'93establish[ing] a new regulatory analytical method\'94 for the drug substance or drug product;}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 7498 (codified at 21 C.F.R. \'a7 314.70(b)(1)(ii)); }{\i\f0\fs20\expnd0\expndtw-2\super id.}{\f0\fs20\expnd0\expndtw-2\super at 7499 (codified at 21 C.F.R. \'a7 314.70(b)(2)(iii)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \'93delet[ing] a specification or regulatory analytical method\'94 for a drug substance or drug product;}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 7498 (codified at 21 C.F.R. \'a7 314.70(b)(1)(iii)); }{\i\f0\fs20\expnd0\expndtw-2\super id.}{\f0\fs20\expnd0\expndtw-2\super at 7499 (codified at 21 C.F.R. \'a7 314.70(b)(2)(iii))..}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \'93chang[ing] the synthesis of the drug substance\'94;}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 7498 (codified at 21 C.F.R. \'a7 314.70(b)(1)(iv)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \'93us[ing] a different facility or establishment to manufacture the drug substance\'94 unless (a) the manufacturing process does not undergo a \'93material[]\'94 change and \'93(b) the new facility or establishment has}{ \f0\fs24\expnd0\expndtw-3 }{\f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt\f3\fs24}}}{\f0\fs24\expnd0\expndtw-3 received a satisfactory current good manufacturing process (CGMP) inspection within the pr evious 2 years covering that manufacturing process\'94;}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 7499 (codified at 21 C.F.R. \'a7 314.70(b)(1)(v)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \'93chang[ing] the method of manufacture of the drug product, including changing or relaxing an in-process control\'94;}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 7499 (codified at 21 C.F.R. \'a7 314.70(b)(2)(v)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 and \'93us[ing] a different facility or establishment, including a different contract laboratory or labeler, to manufacture, process, or pack the drug product.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 7499 (codified at 21 C.F.R. \'a7 314.70(b)(2)(vi)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 As in the 1968 revision, \'93[a]dd[ing] a new specification or test method or changes in the methods, facilities (except a change to a new facility), or controls to provide increased ass urance that the drug will have the [purported or represented] characteristics of identity, strength, quality, and purity\'94 was to be covered by a changes being effected supplement.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 7499 (codified at 21 C.F.R. \'a7 314.70(c)(1).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 In addition, new facilities or establishments not needing premarketing approval under 21 C.F.R. \'a7\~314.70(b)(1)(v) could be brought on-line at the time of the supplement\rquote s filing.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 7499 (codified at 21 C.F.R. \'a7 314.70(c)(3)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par Interestingly, the chemists reasserted themselves in the FDA\rquote s internal battles between the proposed and final regulations. While the pharmaceutical industry believes the proposal contained \'93very good language,\'94 it regards the final rule as \'93a step backwards.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Telephone Interview with Thomas X. White, Associate Vice President for Manufacturing and Quality Control, PhRMA (Jan. 10, 1997) [hereinafter White Interview].}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Prior approval was restored for new contract laboratories and labelers, changes in the synthesis of drug substances, and new facilities and establishments for manufacturing drug substances in certain circumstances.}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See }{\f0\fs20\expnd0\expndtw-2\super 1985 Rewrite, 50 Fed Reg. at 7467.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Nevertheless, the industry had high hopes that the 1985 rewrite would free them to incorporate new manufacturing technologies efficiently, but these hopes were never fully reali zed as the chemists retained control over the implementation of the new regulations.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Vodra Interview, }{\i\f0\fs20\expnd0\expndtw-2\super supra}{\f0\fs20\expnd0\expndtw-2\super note 10.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par }\pard \qc \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\b\fs24\ul 1990: The Lasagna Commission}{\cs18\b\fs24\ul\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0 \nowidctlpar\tx0\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\b\f0\fs18\ul\expnd0\expndtw-2 \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx0\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\b\f0\ul\expnd0\expndtw-2 Formally, the National Committee to Review Current Procedures for Approval of New Drugs for Cancer and AIDS.}{\f0\expnd0\expndtw-2 \par }}}{\b\fs24\ul Report}{\fs24 \par \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 The Lasagna Commission was formed to study possible statutory, regulatory, and administrative \'93 changes that, while preserving protection for patients, would accelerate the\'94 development and marketing of new treatments to cancer and AIDS patients.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0 \nowidctlpar\tx0\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2 \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx0\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2 }{\scaps\f0\expnd0\expndtw-2 National Committee to Review Current Procedures for Approval of New Drugs for Cancer and AIDS, Final Report of the National Committee to Review Current Procedures for Approval of New Drugs for Cancer and AIDS }{\f0\expnd0\expndtw-2 at viii (1990). \par }}}{\fs24\expnd0\expndtw-3 The Commission strongly criticized the FDA\rquote s handling of manufacturing supplements: \'93[S]upplemental NDAs relat[ing] to changes in manufacturing and other technical modifications to an approved NDA}{ \f0\fs24\expnd0\expndtw-3 }{\f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt\f3\fs24}}}{\f0\fs24\expnd0\expndtw-3 consume a great deal of FDA resources to no great social purpose.\'94}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 12.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 It proposed a default rule of approval after 180 days, placing the burden on the agency to provide \'93a detailed an specific reason why the change would result in a safety hazard\'94 to block approval.}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 12-13.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 While neither Congress nor the FDA adopted this proposal, one may presume that it influenced congressional consideration of the Prescription Drug User Fee Act of 1992}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Pub. L. No. 102-571, 106 Stat. 4491 (codified at 21 U.S.C. \'a7\'a7 379g-h (1994)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 (PDUFA) (described below) and placed pressure on the FDA to reduce the burden of its approval process on manufacturers. \par }\pard \qc \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\b\fs24\ul 1992: The Prescription Drug User Fee Act of 1992}{\fs24 \par }\pard \ql \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24 \par \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 By the early 1990s a consensus emerged that the FDA lacked the resources to review product a pplications (including manufacturing supplements) expeditiously. Since \'93[s]upplemental applications for manufacturing changes ha[d]}{\f0\fs24\expnd0\expndtw-3 }{\f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt \f3\fs24}}}{\f0\fs24\expnd0\expndtw-3 traditionally been given a very low priority within the FDA,\'94 it frequently took years for manufacturers to receive premarketing approval.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super }{\scaps\f0\expnd0\expndtw-2\super S. Rep. No. 104-284}{ \f0\expnd0\expndtw-2\super , at 39.}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Recognizing that Congress would not provide the necessary additional resources given concerns about the federal deficit, the pharmaceutical industry agreed to beef up the agency through user fees.}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Cf.}{\f0\fs20\expnd0\expndtw-2\super 21 U.S.C. \'a7\'a7 379g-h (1994).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 In exchange, the industry persuaded Congress to require the FDA to report annually on its progress in meeting statutory goals for timely approvals.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Cf.}{\f0\fs20\expnd0\expndtw-2\super 21 U.S.C. \'a7 379g Note (1994).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par For manufacturing supplements, PDUFA has worked incredibly well. In fiscal year 1995 the Centers for Drug Evaluation and Research and Biolo gics Evaluation and Research combined to review eighty-nine percent of manufacturing supplements within six months of submission (exceeding the statutory goal of seventy percent).}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\scaps\f0\fs20\expnd0\expndtw-2\super Office of Planning and Evaluation, Food and Drug Administration, Fourth Annual Performance Report: Prescription Drug User Fee Act of 1992: Fiscal Year 1996 Report to Congress}{ \f0\fs20\expnd0\expndtw-2\super (Dec. 1, 1996) .}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 During the first six months of fiscal year 1996, the two centers had a combined on-time performance of ninety-six percent, and the FDA projected they would ultimately exceed the eighty percent goal.}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 As a result of this legislation, the premarketing approval process causes much less delay (albeit at the cost of the user fee) fo r companies that want to upgrade their manufacturing technology. No longer will FDA supervisors permit \par the chemists to sit on supplements for a matter of years as they used to do.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super }{\i\f0\expnd0\expndtw-2\super See}{\f0\expnd0\expndtw-2\super White Interview, }{\i\f0\expnd0\expndtw-2\super supra}{\f0\expnd0\expndtw-2\super note 59.}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par }\pard \qc \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\b\fs24\ul 1995: Reinventing Government and the SUPAC}{\fs24 \par }\pard \ql \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24 \par \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 In its effort to demonst rate that New Democrats are business-friendly and opposed to regulation for regulation\rquote s sake, the Clinton Administration launched its Reinventing Government initiative headed by the National Performance Review (NPR) under Vice President Gore. Perhaps reflecting the Vice President\rquote s continued interest in the subject from his service on the House Science Committee in the early 1980s, the NPR included the regulation of drugs and medical devices among its focuses. In the spring of 1995, it issued a report on the reinvention of FDA \rquote s operations in this area.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 { \f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super }{\scaps\f0\expnd0\expndtw-2\super President Bill Clinton & Vice President Al Gore, National Performance Review, Reinventing Regulation of Drugs and Medical Devices (1995). }{\f0\expnd0\expndtw-2\super I will only describe the report\rquote s discussion of drug supplements and not the parallel reforms for biological products since these have a different regulatory history which is outside the scope of this paper.}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Complaining that \'93[m]anufacturers must often wait six to twelve months to receive FDA approval [of a manufacturing supplement], during which time the manufacturers are prevented from making changes to t he product or production facility that they believe are more efficient or otherwise necessary,\'94 the report stated, \'93FDA will reduce the number of changes that require pre-approval.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 7.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 The report then explained that the agency\rquote s CDER was \'93developing a guidance document for drugs in tablet and capsule form (other than those for controlled release)}{\f0\fs24\expnd0\expndtw-3 }{ \f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt\f3\fs24}}}{\f0\fs24\expnd0\expndtw-3 [which] would distinguish changes that are unlikely to have any detectable impact on a drug product\rquote s quality and performance from those that could have a significant impact.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 (In addition, the FDA was to issue \'93similar guidance document[s] for other dosage forms\'94 by the end of 1996.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id. }{\f0\fs20\expnd0\expndtw-2\super at 9.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 ) \par As promised, the FDA released the guidance document for immediate release drugs (the SUPAC Guidance) in November 1995.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super SUPAC Guidance, 60 Fed. Reg. at 61638. However, as of January 15, 1997, the agency had not published guidance for other dosage forms. On the other hand, as of May 1996, the FDA was reportedly finalizing these documents. Wechsler, }{\i\f0\fs20\expnd0\expndtw-2\super supra}{ \f0\fs20\expnd0\expndtw-2\super note 17, at 22.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 The regulations on supplements direct applicants to follow \'93a guideline, notice, or regulation published in the Federal Register that provides for a less burdensome notification of the change\'94 than required by the regulations themselves.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 { \f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super 21 C.F.R. \'a7 314.70(a) (1996).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 The SUPAC Guidance invoked this provision to reduce the reporting requirements for changes including those in manufacturing sites, changes in batch size, and manufacturing processes.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See }{\f0\fs20\expnd0\expndtw-2\super SUPAC Guidance, 60 Fed. Reg. at 61638, 61641-42. Interestingly, however, the FDA also insists that the \'93 guidance is an informal communication under 21 CFR 10.90(b)(9) that reflects the best judgment of CDER employees at this time. }{\i\f0\fs20\expnd0\expndtw-2\super It does not create or confer any rights, privileges, or benefits for or on behalf of any person, nor does it operate to bind or obligate FDA in any way.}{\f0\fs20\expnd0\expndtw-2\super \'94 }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 61638.}{ \f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par The SUPAC Guidance divided site changes into three \'93levels\'94 and emphasized that such changes should ordinarily not demand premarketing approval of a supplement.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super However, site changes \'93do not include }{\f0\fs20\expnd0\expndtw-2\super {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 10}{\fldrslt\f3\fs20}}}{\f0\fs20\expnd0\expndtw-2\super changes in manufacturing (including process and/or equipment),\'94 and \'93[n]ew manufacturing locations [still] should have a satisfactory current good manufacturing practice (CGMP) inspection.\'94 }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{ \f0\fs20\expnd0\expndtw-2\super at 61641. Of course, these two exceptions were the ones that triggered premarketing approval requirements for drug substances under the 1985 Rewrite, 50 Fed. Reg. at 7499 (codified at 21 C.F.R. \'a7 314.70(b)(1)(v)).}{ \f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Level 1 changes, which manufacturers may merely notice in their annual reports, \par \par }\pard \qj \fi-540\li540\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin540\itap0 {\fs24\expnd0\expndtw-3 \tab consist of site changes within a single facility where the same equipment, standard operating proce dures}{\f0\fs24\expnd0\expndtw-3 }{\f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt\f3\fs24}}}{\f0\fs24\expnd0\expndtw-3 , environmental conditions }{\f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt\f3\fs24}}}{\f0\fs24\expnd0\expndtw-3 and controls, and personnel common to both manufacturing sites are used, and where no changes are made to the manufacturing batch records [with two exceptions]. Common is defined as employees already working on the camp us who have suitable experience with the manufacturing process.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super SUPAC Guidance, 60 Fed. Reg. at 61641.}{ \f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 Level 2 changes, which require a changes being effected supplement as well as annual reporting of long-term stability test data, \'93consist of site changes within a contiguous campus, or between facilities in adjacent city blocks.\'94}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super }{\i\f0\expnd0\expndtw-2\super Id.}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Otherwise, they have the same limits as Level 1 changes.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Level 3 changes, which require the same reporting as Level 2 changes, \'93consist of a change in manufacturing site to a}{\f0\fs24\expnd0\expndtw-3 }{\f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt\f3\fs24}}}{\f0\fs24\expnd0\expndtw-3 campus }{\f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt\f3\fs24}}}{\f0\fs24\expnd0\expndtw-3 that is not on the same ori ginal continuous site or where the facilities are not in adjacent city blocks.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Otherwise, they also have substantially the same limits as Level 1 changes.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 While not substantially changing the requirements for drug substances,}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See}{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super supra }{\f0\fs20\expnd0\expndtw-2\super note 54 and accompanying text.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 the SUPAC Guidance did significantly liberalize the rules for drug products, for which the 1985 Rewrite insisted upon premarketing approval for new manufacturing facilities and establishments.}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See}{\f0\fs20\expnd0\expndtw-2\super 1985 Rewrite, 50 Fed. Reg. at 7499 (codified at 21 C.F.R. \'a7 314.70(b)(2)(vi)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par \par The SUPAC Guidance also clarified that changes in batch size do not require premarketing approval, provided that the batch does not fall below 100,000 dosage units; \par }\pard \ql \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin0\itap0 {\fs24 \par \par }\pard \qj \fi-540\li540\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin540\itap0 {\fs24\expnd0\expndtw-3 \tab [t]he equipment used to produce the test batch(es) is of the same design and operating principles;}{ \f0\fs24\expnd0\expndtw-3 }{\f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt\f3\fs24}}}{\f0\fs24\expnd0\expndtw-3 the batch(es) is (are) manufactured in full compliance with CGMP\rquote s; and }{ \f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt\f3\fs24}}}{\f0\fs24\expnd0\expndtw-3 the same SOP\rquote s and controls, as well as the same formulation and manufacturing procedures, are used on the test batch(es) and on the full-scale production batch(es).}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0 \nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super SUPAC Guidance, 60 Fed. Reg. at 61641.}{ \f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 Changes of up to a factor of 10 in the approved batch size (Level 1) need only be listed in the annual report}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super }{\i\f0\expnd0\expndtw-2\super Id.}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 while manufacturers must file a changes being effected supplement for all other changes (Level 2).}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id. }{\f0\fs20\expnd0\expndtw-2\super at 61642.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Manufacturers must also provide long-term stability data for Level 2 changes in the annual report.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par \par Instead of requiring premarketing approval for all changes in equipment type, the SUPAC Guidance also permits annual reporting of (1) the automation of ingredient-moving equipment and (2) equipment changes that do not alter the equipment\rquote s design or operating principles (Level 1).}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 { \f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super }{\i\f0\expnd0\expndtw-2\super Id.}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Manufacturers still must receive premarketing approval for Level 2 equipment changes (\'93to a different design and different operating principles\'94).}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par Likewise, the SUPAC Guidance reduced the premarketing approval requirement for certain manufacturing process changes. Level 1 process changes (those that retain the same basic process and remain \'93within application/validation ranges\'94 ) are to be noted in annual reports.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 { \f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 When manufacturers retain the same basic process but move outside these ranges (Level 2), they must file a changes being effected supplement.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Finally, \'93change[s] in the type of process used\'94 (Level 3) cause the company to have to file a supplement and wait for premarketing approval.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par The SUPAC Guidance was \'93\lquote a sea change in FDA operations\rquote [since it was] the first time the agency has internally generated serious deregulation.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Wechsler, }{\i\f0\fs20\expnd0\expndtw-2\super supra }{\f0\fs20\expnd0\expndtw-2\super note 17, at 20 (quoting Gary Hollenbeck, Associate Dean of Maryland\rquote s School of Pharmacy).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 It should eliminate about twenty percent of the roughly 1,200 manufacturing supplements the FDA used to receive annually.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0 \nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2\super at 22.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Moreover, the guidance has clarified what data and documentation the agency expects from manufacturers for each type of change \emdash a marked contrast from the frequent uncertainty of the past.}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par }\pard \qc \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\b\fs24 EUROPEAN UNION PROCEDURES}{\fs24 \par }\pard \ql \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24 \par \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqc\tx4680\tqr\tx9360\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 The European Union requires premarketing approval for all \'93variations\'94 (a supplement) to \'93 marketing authorizations\'94 (approved NDAs). While formally this procedure is more restrictive than the American practice, the EU commits to providing approvals or disapprovals much more rapidly than the FDA, so companies can mak e many manufacturing changes in Europe earlier than in the United States. On the other hand, they may have to devote greater resources to applying for European variations since the U.S. annual reporting procedure for insignificant alterations is less bur densome than filing a supplemental NDA.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 { \f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super Cf. }{\scaps\f0\expnd0\expndtw-2\super Clinton & Gore}{ \f0\expnd0\expndtw-2\super , }{\i\f0\expnd0\expndtw-2\super supra}{\f0\expnd0\expndtw-2\super note 73, at 8 (noting that the SUPAC and other guidance documents will enable companies to \'93 sav[e] resources that would have been spent on preparing supplemental applications\'94 by switching to annual reporting). The comparative paperwork burden would actually depend upon the relative complexity of the notification and justification that the EU and the U.S. FDA require companies to provide in supplements/variations or annual reports. As this question is beyond th e scope of this paper, I am merely pointing out that the European procedures may not be uniformly more favorable to industry.}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par The EU has two different methods of approving marketing authorization applications, a decentralized (but concerted) procedure conducted by the various national regulatory authorities and a centralized procedure run by the European Medicines Evaluation Agency (EMEA).}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See}{\f0\fs20\expnd0\expndtw-2\super Council Regulation 2309/93, arts. 1-18, 1993 O.J. (L 214), }{\i\f0\fs20\expnd0\expndtw-2\super available in }{\f0\fs20\expnd0\expndtw-2\super LEXIS, Intlaw Library, ECLaw File (establishing the centralized procedure); Council Directive 93/39/EEC, 1993 O.J. (L 214), }{\i\f0\fs20\expnd0\expndtw-2\super available in }{\f0\fs20\expnd0\expndtw-2\super LEXIS, Intlaw Library, ECLaw File (establishing the current decentralized procedure); }{\i\f0\fs20\expnd0\expndtw-2\super see generally }{\f0\fs20\expnd0\expndtw-2\super Richard F. Kingham et al., }{\i\f0\fs20\expnd0\expndtw-2\super The New European Medicines Agency}{\f0\fs20\expnd0\expndtw-2\super , 49 }{\scaps\f0\fs20\expnd0\expndtw-2\super Food & Drug L.J.}{\f0\fs20\expnd0\expndtw-2\super 301, 304-13 (1994) (describing both); Robin Madell, }{\i\f0\fs20\expnd0\expndtw-2\super Tour Through a Work in Progress}{\f0\fs20\expnd0\expndtw-2\super , }{\scaps\f0\fs20\expnd0\expndtw-2\super Pharmaceutical Executive, }{\f0\fs20\expnd0\expndtw-2\super Jan. 1996, at 38, 39 (briefly summarizing both processes).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Separate regulations provide for variations to marketing authorizations granted under each of the procedures.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See}{\f0\fs20\expnd0\expndtw-2\super Commission Regulation 542/95, 1995 O.J. (L 55), }{\i\f0\fs20\expnd0\expndtw-2\super available in }{\f0\fs20\expnd0\expndtw-2\super LEXIS, Intlaw Library, ECLaw File (establishing the centralized procedure); Commission Regulation 541/95, 1995 O.J. (L 55), }{\i\f0\fs20\expnd0\expndtw-2\super available in }{\f0\fs20\expnd0\expndtw-2\super LEXIS, Intlaw Library, ECLaw File (establishing the decentralized procedure); }{\scaps\f0\fs20\expnd0\expndtw-2\super Directorate-General III, European Commission, Doc. No. }{\f0\fs20\expnd0\expndtw-2\super III/5371/96, }{ \scaps\f0\fs20\expnd0\expndtw-2\super Draft Notice to Applicants for Marketing Authorisations for Medicinal Products for Human Use in the European Union}{\f0\fs20\expnd0\expndtw-2\super , ch. v, }{\i\f0\fs20\expnd0\expndtw-2\super available in}{ \f0\fs20\expnd0\expndtw-2\super IHS Regulatory Products, Inc., FDL/EUPL database, issue 96-12 [hereinafter }{\scaps\f0\fs20\expnd0\expndtw-2\super Draft Notice to Applicants}{\f0\fs20\expnd0\expndtw-2\super ], }{\i\f0\fs20\expnd0\expndtw-2\super replaced by }{\scaps\f0\fs20\expnd0\expndtw-2\super Doc. No. }{\f0\fs20\expnd0\expndtw-2\super III/5429/96 (which I was unable to obtain) (providing detailed guidelines for both procedures).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 However, the basic principles underlying both procedures are identical. The EU divide s changes to marketing authorizations into three categories: minor (type I) variations, major (type II) variations, and changes that are so fundamental as to require separate marketing authorizations.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See}{\f0\fs20\expnd0\expndtw-2\super Commission Regulation 542/95, art. 3, Annex II; Commission Regulation 541/95, art. 3, Annex II.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par The Commission regulations give the relevant regulatory authorities sixty days to act on a major variation}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Major variations are defined as variations not listed in the annexes. }{\i\f0\fs20\expnd0\expndtw-2\super See }{\f0\fs20\expnd0\expndtw-2\super Commission Regulation 542/95, art. 3, \'b6 1(b); Commission Regulation 541/95, art. 3, \'b6 1(b).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 application (although they may ask the applicant for additional information one time which adds another sixty days to the clock).}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0 \nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See }{\f0\fs20\expnd0\expndtw-2\super Commission Regulation 542/95, art. 7; Commission Regulation 541/95, art. 7.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 But, this guideline appears to be hortatory since major variations do not take effect without actual (as opposed to constructive) regulatory approval.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See }{\f0\fs20\expnd0\expndtw-2\super Commission Regulation 542/95, arts. 6-8; Commission Regulation 541/95, arts. 6-7.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par For minor variations, the relevant regulatory authority or authorities have thirty days to disapprove the application and \'93stat[e] the objective grounds on which its opinion is based.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Commission Regulation 542/95, art. 5; Commission Regulation 541/95, art. 5. The 30-day clock does not start running immediately. Under the centralized procedure, the EMEA Secretariat has five worki ng days to validate the application\rquote s completeness; only at this point does the clock start. }{\scaps\f0\fs20\expnd0\expndtw-2\super Draft Notice to Applicants}{\f0\fs20\expnd0\expndtw-2\super , }{\i\f0\fs20\expnd0\expndtw-2\super supra }{ \f0\fs20\expnd0\expndtw-2\super note 102, ch. v, \'a7 4.4(d). Under the decentralized procedure, the \'93reference\'94 Member State (the country principally responsible for the authorization) starts the clock. }{\i\f0\fs20\expnd0\expndtw-2\super Id.}{ \f0\fs20\expnd0\expndtw-2\super \'a7 3.1.1.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 If the application is not disapproved within thirty days, it is deemed to be approved.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See }{\f0\fs20\expnd0\expndtw-2\super Commission Regulation 542/95, art. 5; Commission Regulation 541/95, art. 5.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Minor variations are, thus, roughly equivalent to changes being effected supplements in the United States in that manufacturers may implement the changes relatively quickly. However, minor variations offer companies greater certainty since they will be approved within thirty days one way or another while the FDA can always disapprove a changes being effected supplement up to six months (or even la ter) after it is filed.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 { \f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Cf. supra }{\f0\fs20\expnd0\expndtw-2\super text accompanying notes 67-72.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par In their respective first annexes, Commission Regulations 542/95 and 541/95 set out the list of possible minor variations along with the conditions that the marketing authorization holders must demonstrate to win acceptance of t he variation. Changes in the manufacturer(s) of active substances are minor variations provided that \'93 the specifications, synthetic route and quality control procedures are the same as those already approved or a European Pharmacopoeia Certificate of suitability covering the active substance is submitted.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Commission Regulation 542/95, Annex I, \'b6 11; Commission Regulation 541/95, Annex I, \'b6\~11.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 , Minor changes of the manufacturing processes of active substances are minor variations if the substance\rquote s \'93[s]pecifications are not adversely affected; [and there is] no change in the physical properti es [and] no impurities or change in level of impurities which would require further qualifications in safety studies.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Commission Regulation 542/95, Annex I, \'b6 12; Commission Regulation 541/95, Annex I, \'b6\~12.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 An alteration of the batch size of the active substance is a minor variation so long as \'93the change does not affect consistency of production}{\f0\fs24\expnd0\expndtw-3 }{\f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt\f3\fs24}}}{\f0\fs24\expnd0\expndtw-3 or physical properties.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Commission Regulation 542/95, Annex I, \'b6 13; Commission Regulation 541/95, Annex I, \'b6\~13.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 A change in the specifications of the active substance or of the medicinal product that tightens the specifications or adds new tests or limits is a minor variation.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See }{\f0\fs20\expnd0\expndtw-2\super Commission Regulation 542/95, Annex I, \'b6\'b6 14, 17; Commission Regulation 541/95, Annex I, \'b6\'b6\~14, 17.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Changes in the manufacture of the medicinal product are minor variations when \'93[m]edicinal product specifications are not adversely affected; [and] the new process}{\f0\fs24\expnd0\expndtw-3 }{\f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt\f3\fs24}}}{\f0\fs24\expnd0\expndtw-3 lead[s] to an identical product regarding all aspects of quality, safety and efficacy.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Commission Regulation 542/95, Annex I, \'b6 15; Commission Regulation 541/95, Annex I, \'b6\~15.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Changes in the batch size of the finished product are minor variations provided they \'93do[] not affect consistency of production.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Commission Regulation 542/95, Annex I, \'b6 16; Commission Regulation 541/95, Annex I, \'b6\~16.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Changes in the test procedures of the active substance or the medicinal product are minor variations if they do not reduce the potency of the test or (for medicinal products) adversely affect the product\rquote s specifications.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 { \f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See }{\f0\fs20\expnd0\expndtw-2\super Commission Regulation 542/95, Annex I, \'b6\'b6 24-25; Commission Regulation 541/95, Annex I, \'b6\'b6 24-25. Annex I also lists further minor variations that are less relevant to this paper.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par This list of minor variations includes a number of changes that would require premarketing approval of a supplement in the United States. For example, consider a change in the basic type of manufacturing p rocess of the medicinal product that does not adversely affect the product\rquote s specifications or produce some difference in the drug relevant to quality, safety, or efficacy. It would be a Level 3 manufacturing change under the SUPAC Guidance, requiring premarketing approval of a supplement, in the United States.}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See}{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super supra }{\f0\fs20\expnd0\expndtw-2\super note 96 and accompanying text.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 In Europe it would be a minor variation and would be permitted unless disapproved within thirty days.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See}{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super supra }{\f0\fs20\expnd0\expndtw-2\super note 114 and accompanying text.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Likewise, changes in test procedures must provide enhanced accuracy to qualify for a changes being effected supplement in the United States but must merely be equivalent to be a minor variation in the EU.}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See}{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super supra }{\f0\fs20\expnd0\expndtw-2\super notes 57, 116 and accompanying text.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Indeed, in the 1985 Rewrite, the FDA specifically rejected equivalence as the touchstone for not requiring premarketing approval of the supplement: Changes that \par \par }\pard \qj \fi-540\li540\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin540\itap0 {\fs24\expnd0\expndtw-3 \tab giv[e] increased assurance that the drug will possess its represented characteristics}{ \f0\fs24\expnd0\expndtw-3 }{\f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt\f3\fs24}}}{\f0\fs24\expnd0\expndtw-3 can be made without prior approval because, by assuring to a greater degree that the drug will possess its represented characteristics, the chang e provides a public health benefit. A change that provides only the same level of assurance, however, does not provide such a benefit and, thus, the agency finds no basis for \par }\pard \ql \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin0\itap0 {\f0\fs24 \par }\pard \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin0\lin0\itap0 {\f0\fs24\expnd0\expndtw-3 allowing manufacturers to report such alterations in a changes being effected supplement.}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super 1985 Rewrite, 50 Fed. Reg. at 7468-69.}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par \par Thus, the EU\rquote s procedures provide companies with more flexibility than the FDA allows. This conclusion leads to three key questions. First, is more flexibility desirable? Second, will current legislative proposals provide this flexibili ty? Third, is the FDA institutionally capable of meeting such a command? \par }\pard \ql \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin0\lin0\itap0 {\fs24 \par }\pard \qc \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqr\tx9360\hyphpar0\faauto\rin0\lin0\itap0 {\b\fs24 CURRENT PROPOSALS TO AMEND THE AMERICAN REGULATIONS}{\fs24 \par }\pard \ql \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqr\tx9360\hyphpar0\faauto\rin0\lin0\itap0 {\fs24 \par \par }\pard \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tqr\tx9360\hyphpar0\faauto\rin0\lin0\itap0 {\fs24\expnd0\expndtw-3 In some cases, the FDA\rquote s rules governing manufacturing changes probably should be loosened.}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super I am deliberately making these conclusions tentative. I do not yet feel that I understand all the ramifications of making manufacturing changes, so I cannot make confident pronouncements about the appropriate level of review for any particular one.}{ \f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 For instance, manufacturers s hould only have to notice changes in test procedures that provide equivalent or enhanced accuracy in their annual reports rather than in premarketing and changes being effected supplements, respectively. If companies can deliver the same (let alone bette r) levels of quality assurance with less expensive methods, we should encourage, not discourage, them from doing so. Likewise, the FDA should probably adopt a version of the EU\rquote s minor variation procedure for reviewing changes in the basic types of drug manufacturing processes which do not adversely affect the products\rquote specifications or produce some difference in the drugs\rquote identity, strength, quality, purity or potency relating to the medicines\rquote safety or efficacy. While some form of premarketing approv al seems appropriate given a wholesale revamping of the process, full-scale reviews would probably not deliver benefits commensurate with their costs since the products (by definition) remain within specifications and do not change materially. \par Last summer, FDA, PhRMA, and congressional negotiators reached a tentative \'93meeting of the minds\'94 on new legislative language on manufacturing changes.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super White Interview, }{\i\f0\fs20\expnd0\expndtw-2\super supra}{\f0\fs20\expnd0\expndtw-2\super note 59. Mr. White emphasized that PhRMA did not consider this agreement to be permanently binding and that the industry would pursue further changes in the 105th Congress. }{\i\f0\fs20\expnd0\expndtw-2\super See id.}{\f0\fs20\expnd0\expndtw-2\super ; }{\i\f0\fs20\expnd0\expndtw-2\super see}{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super generally Text of PhRMA Draft FDA Reform Proposal}{\f0\fs20\expnd0\expndtw-2\super , }{\scaps\f0\fs20\expnd0\expndtw-2\super Inside Washington \rquote s FDA Week}{\f0\fs20\expnd0\expndtw-2\super , Jan. 10, 1997, at S1, S8 [hereinafter }{\i\f0\fs20\expnd0\expndtw-2\super PhRMA Draft}{\f0\fs20\expnd0\expndtw-2\super ] (text of proposed sec. 19, \'a7 505(n)).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 This agreement would preserve the three tiers but alter the middle one (changes being effected supplements) to require the applicant to wait for thirty days before distributing the drug prior to approval.}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See}{\f0\fs20\expnd0\expndtw-2\super Amendment to H.R. 3199, 104th Cong. sec. 12, \'a7 741(b)(2) (staff discussion draft of Jul. 10, 1996) [hereinafter Staff Discussion Draft]. The Secretary could block implementation after 30 days by informing the applicant that premarketing approval is required. }{\i\f0\fs20\expnd0\expndtw-2\super See }{\f0\fs20\expnd0\expndtw-2\super sec. 12, \'a7\~741(b)(2)(C). The more recent PhRMA proposal lengthens the waiting period to 60 days. }{\i\f0\fs20\expnd0\expndtw-2\super See PhRMA Draft}{\f0\fs20\expnd0\expndtw-2\super , sec. 19, \'a7 505(n)(2)(C).}{ \f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 It would permit annual reporting of changes \'93of a type determined by the Secretary to have minimal potential to adversely affect the identity, strength, qualit y, purity, or potency as they may relate to the safety or effectiveness of a drug.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Staff Discussion Draft, sec. 12, \'a7 741(b)(2)(A); }{\i\f0\fs20\expnd0\expndtw-2\super see also}{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super PhRMA Draft}{\f0\fs20\expnd0\expndtw-2\super , sec. 19, \'a7 505(n)(2)(A) (removing the Secretary\rquote s determination: \'93of a type that have minimal potential\'94).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Such changes would include \'93add[ing] a new specification(s) or test method(s) or control(s) to provide increased assurance that the drug will have the [represented or pur ported] characteristics of identify (sic), strength, quality, and purity\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Manufacturing Changes Report Language: Consensus Report Language, Sec. 604 of S. 1477, at 1, 1 (July 8, 1996 draft) (obtained from Matthew B. Van Hook, Assistant General Counsel, PhRMA).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \emdash improvements that now require a changes being effected supplement.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See}{\f0\fs20\expnd0\expndtw-2\super 21 C.F.R. \'a7 314.70(c)(1) (1996).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 The agreement would retain a premarketing approval supplement for changes \'93of a type determined by the Secreta ry to have a substantial potential to adversely affect the identity, strength, quality, purity, or potency as they may relate to the safety or effectiveness of a drug.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Staff Discussion Draft, sec. 12, \'a7 741(b)(2)(B); }{\i\f0\fs20\expnd0\expndtw-2\super see also}{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super PhRMA Draft}{\f0\fs20\expnd0\expndtw-2\super , sec. 19, \'a7 505(n)(2)(B) (removing the Secretary\rquote s determination: \'93of a type that have a substantial potential\'94).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Such \par \par }\pard \qj \fi-540\li540\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin540\itap0 {\fs24\expnd0\expndtw-3 \tab [m]ajor manufacturing changes are (i) changes in the qualitative or quantitati ve formulation or the specifications in the approved marketing application (unless exempted by the Secretary); (ii) changes which the Secretary determines by regulation or guidance require completion of an appropriate human study demonstrating equivalence to the drug manufactured before such changes; and (iii) other changes which the Secretary determines by regulation or guidance have a substantial potential to adversely affect the safety or effectiveness of the drug.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super Staff Discussion Draft, sec. 12, \'a7 741(b)(2)(B); }{\i\f0\expnd0\expndtw-2\super see also}{\f0\expnd0\expndtw-2\super }{\i\f0\expnd0\expndtw-2\super PhRMA Draft}{\f0\expnd0\expndtw-2\super , sec. 19, \'a7 505(n)(2)(B) (requiring determinations by regulation rather than by regulation or guidance).}{ \f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 All other changes would fall in the ne w mid-level tier, requiring a thirty day delay during consideration of the supplement before implementation of the change unless the change falls in a class determined by the Secretary to be implementable at the time of submission.}{ \cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super }{\i\f0\expnd0\expndtw-2\super See}{\f0\expnd0\expndtw-2\super Staff Discussion Draft. sec. 12, \'a7 741(b)(2)(C); }{\i\f0\expnd0\expndtw-2\super see also PhRMA Draft}{\f0\expnd0\expndtw-2\super , sec. 19, \'a7\~505(n)(2)(C) (requiring a 60 day delay).}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par \par With the exception of permitting annual reporting of specification, testing, or control improvements,}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super }{\i\f0\expnd0\expndtw-2\super See supra}{\f0\expnd0\expndtw-2\super notes 124-25 and accompanying text.}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 this legislation will not ensure that the FDA loosens its grip on manufacturing changes. It reasonably permits the agency to define the classes of variations that \'93have a substantial potential to adversely affect the safety or effectiveness of the drug.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super Staff Discussion Draft, sec. 12, \'a7 741(b)(2)(B)(iii); }{\i\f0\fs20\expnd0\expndtw-2\super see also}{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super PhRMA Draft}{\f0\fs20\expnd0\expndtw-2\super , sec. 19, \'a7\~505(n)(2)(B)(iii) (requiring determinations by regulation rather than by regulation or guidance).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 Under Supreme Court precedents such definitions will be virtually unreviewable by courts,}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar \tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See Sullivan v. Zebley}{\f0\fs20\expnd0\expndtw-2\super , 493 U.S. 521, 528 (1990) (holding that, when Congress expressly delegates legislative authority, \'93 our review is limited to determining whether the regulations promulgated exceeded the Secretary\rquote s statutory authority and whether they are arbitrary and capricious\'94 (internal quotation marks omitted)); }{\i\f0\fs20\expnd0\expndtw-2\super Chevron, U.S.A., Inc. v. Natural Resources Defense Council, Inc.}{\f0\fs20\expnd0\expndtw-2\super , 467 U.S. 837, 842-43 (1984) (holding that, in the face of statutory ambiguity, courts should defer to any \'93permissible construction of the statute\'94 by the agency).}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 so the FDA will retain the legal power to do as it chooses. Whether the FDA chooses to relax further will depend upon changes to its institutional culture. As discussed above, the agency has recently begun to shed its conservatism about risk;}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super See supra}{\f0\fs20\expnd0\expndtw-2\super text accompanying notes 16-18.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 if this trend continues, it will promote manufacturing changes more than any legislative fix. \par Finally, the proposed legislation does not address manufacturers\rquote fears that they will implement a change under a changes being affected supplement only to have the FDA disapprove the supplement down the road. It does not follow the European ap proach for minor variations and deem applications not disapproved within a fixed period to be approved.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }{\f0\fs20\expnd0\expndtw-2\super }{\i\f0\fs20\expnd0\expndtw-2\super Compare }{\f0\fs20\expnd0\expndtw-2\super Commission Regulation 542/95, art. 5, }{\i\f0\fs20\expnd0\expndtw-2\super and}{\f0\fs20\expnd0\expndtw-2\super Commission Regulation 541/95, art. 5, }{\i\f0\fs20\expnd0\expndtw-2\super with}{\f0\fs20\expnd0\expndtw-2\super Staff Discussion Draft. sec. 12, \'a7 741(b)(2)(C), }{\i\f0\fs20\expnd0\expndtw-2\super and PhRMA Draft}{\f0\fs20\expnd0\expndtw-2\super , sec. 19, \'a7 505 (n)(2)(C). Even if the proposed legislation did follow the European approach, it is far from clear that the FDA has the institutional capacity to make meaningful decisions within one or two months. I have not investigated this question, but any legislat ive consideration of matching the European standards would be meaningless without an answer.}{\f0\fs20\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 In any event, it is unclear that moving to the European approach would actually provide any greater security for manufacturers that their investments in change will not be wasted. Currently, \par \par }\pard \qj \fi-540\li540\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin540\itap0 {\fs24\expnd0\expndtw-3 \tab [i]f FDA refuses to approve a supplement for a change that the applicant has already placed into effect, the agency must consider all the factors surrounding its refusal to approve the supplement, including the applicant\rquote s reasons for making the change and the alternatives available to the applicant to resolve the problem.}{\f0\fs24\expnd0\expndtw-3 }{\f0\fs24\expnd0\expndtw-3 {\field{\*\fldinst SYMBOL 188 \\f "Symbol" \\s 12}{\fldrslt\f3\fs24}}}{ \f0\fs24\expnd0\expndtw-3 [I]f circumstances warrant, [applicants] may be required to discontinue the change immediately. Nonetheless, if circumstances permit, FDA ag rees that applicants should be able to correct a problem at minimal expense and without unnecessary waste.}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super 1985 Rewrite, 50 Fed. Reg. at 7470.}{ \f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par }\pard \qj \li0\ri540\sl240\slmult0\nowidctlpar\tx0\tx540\tx1080\tx1620\tx2160\hyphpar0\faauto\rin540\lin0\itap0 {\fs24\expnd0\expndtw-3 Thus, present policy is not absolutely rigid, and the European approach would not provide an absolute safe harbor since the FDA would still have the authority to withdraw approval of the NDA (as amended by the supplement) if it determines that \'93 the methods used in, or the facilities and controls used for, the manufacture, processing, and packing of such drug are inadequate to preserve its identity, strength, quality, and purity.\'94}{\cs18\fs24\expnd0\expndtw-3\super \chftn {\footnote \pard\plain \s17\qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs24\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\fs18\expnd0\expndtw-2\super \par }\pard\plain \qj \li0\ri0\sl240\slmult0\nowidctlpar\tx-720\hyphpar0\faauto\rin0\lin0\itap0 \f2\fs20\lang1033\langfe1033\cgrid\langnp1033\langfenp1033 {\f0\expnd0\expndtw-2\super 21 U.S.C. \'a7 355(e).}{\f0\expnd0\expndtw-2 \par }}}{\fs24\expnd0\expndtw-3 \par \par It should not surprise one that enacting partial legislative changes will have no assured effect on agency behavior. The Federal Food, Drug, and Cosmetic Act is amazingly open-textured }{\i\fs24\expnd0\expndtw-3 because}{\fs24\expnd0\expndtw-3 Congress cannot and does n ot dare micromanage food and drug regulation. It lacks the expertise and the time to legislate in the detail necessary to force the agency to act in a certain way. Just as importantly, members of Congress know that such statutory micromanagement would d eprive the FDA of the ability to react to food and drug emergencies; our public health depends on the statute\rquote s open texture. As a result, the agency\rquote s treatment \par of manufacturing changes will depend, as it always has, on the answer to one question: Whither the chemists? \par }}