Editing Food and Drug Administration (section)

==21st-century reforms==

===Critical Path Initiative===
The Critical Path Initiative<ref>{{cite web |url=https://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/default.htm |title=Critical Path Initiative | author = Office of the Commissioner |publisher=Food and Drug Administration |date=February 8, 2019 |access-date=December 16, 2019 |archive-date=April 22, 2019 |archive-url=https://web.archive.org/web/20190422171814/https://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/default.htm |url-status=live}}</ref> is the FDA's effort to stimulate and facilitate a national effort to modernize the sciences through which FDA-regulated products are developed, evaluated, and manufactured. The Initiative was launched in March 2004, with the release of a report entitled Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products.<ref>{{cite web | url = https://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/ucm077262.htm | title = Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products | archive-url = https://wayback.archive-it.org/7993/20180125032208/https://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/ucm077262.htm | archive-date=January 25, 2018 | publisher = U.S. Food and Drug Administration | access-date = August 30, 2012 }}</ref>

===Patients' rights to access unapproved drugs===
The [[Compassionate Investigational New Drug program]] was created after ''Randall v. U.S.'' ruled in favor of [[Robert C. Randall]] in 1978, creating a program for [[medical marijuana]].<ref>{{cite web |url=https://www.vice.com/en/article/the-us-government-has-sent-this-guy-300-joints-each-month-for-34-years/ |title=The US Government Has Sent This Guy 300 Joints Each Month for 34 Years |date=September 9, 2016 |access-date=October 14, 2017 |archive-date=October 14, 2017 |archive-url=https://web.archive.org/web/20171014142910/https://www.vice.com/en_us/article/dp3e4y/the-us-government-has-sent-this-guy-300-joints-each-month-for-34-years |url-status=live}}</ref>

A 2006 court case, ''[[Abigail Alliance v. von Eschenbach]]'', would have forced radical changes in FDA regulation of unapproved drugs. The Abigail Alliance argued that the FDA must license drugs for use by terminally ill patients with "desperate diagnoses", after they have completed Phase I testing.<ref>{{cite web |url=http://www.abigail-alliance.org/WLF_FDA.pdf |title=Abigail Alliance Citizen Petition to FDA |access-date=March 11, 2007 |archive-url=https://web.archive.org/web/20070221153207/http://abigail-alliance.org/WLF_FDA.pdf |archive-date=February 21, 2007}}&nbsp;{{small|(119&nbsp;KB)}}</ref> The case won an initial appeal in May 2006, but that decision was reversed by a March 2007 rehearing. The [[US Supreme Court]] declined to hear the case, and the final decision denied the existence of a right to unapproved medications.

[[Criticism of the Food and Drug Administration|Critics]] of the FDA's regulatory power argue that the FDA takes too long to approve drugs that might ease pain and human suffering faster if brought to market sooner. The AIDS crisis created some political efforts to streamline the approval process. However, these limited reforms were targeted for AIDS drugs, not for the broader market. This has led to the call for more robust and enduring reforms that would allow patients, under the care of their doctors, access to drugs that have passed the first round of clinical trials.<ref>{{cite book | vauthors = Madden BJ |url=https://archive.org/details/freetochoosemedi0000madd |title=Free To Choose Medicine: How Faster Access to New Drugs Would Save Countless Lives and End Needless Suffering: Bartley J. Madden: 9781934791325: Amazon.com: Books |date=July 2010 |publisher=Heartland Institute |isbn=978-1-934791-32-5}}</ref><ref>{{cite news |url=https://www.wsj.com/articles/SB10001424052702303812104576441610360466984 |work=The Wall Street Journal | vauthors = Boldrin M, Swamidass SJ |title=A New Bargain for Drug Approvals |date=July 25, 2011 |url-access=subscription |access-date=August 3, 2017 |archive-date=July 9, 2017 |archive-url=https://web.archive.org/web/20170709173632/https://www.wsj.com/articles/SB10001424052702303812104576441610360466984 |url-status=live}}</ref>

===Post-marketing drug safety monitoring===
The widely publicized recall of [[Vioxx]], a [[non-steroidal anti-inflammatory drug]] (NSAID) now estimated to have contributed to fatal [[myocardial infarction|heart attacks]] in thousands of Americans, played a strong role in driving a new wave of safety reforms at both the FDA rulemaking and statutory levels. The FDA approved Vioxx in 1999, and initially hoped it would be safer than previous NSAIDs due to its reduced risk of intestinal tract bleeding. However, a number of pre and post-marketing studies suggested that Vioxx might increase the risk of myocardial infarction, and results from the APPROVe trial in 2004 conclusively demonstrated this.<ref>{{cite journal | vauthors = Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA | title = Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial | journal = The New England Journal of Medicine | volume = 352 | issue = 11 | pages = 1092–1102 | date = March 2005 | pmid = 15713943 | doi = 10.1056/NEJMoa050493 | s2cid = 8161299 | doi-access = free }}</ref>

Faced with numerous lawsuits, the manufacturer voluntarily withdrew it from the market. The example of Vioxx has been prominent in an ongoing debate over whether new drugs should be evaluated on the basis of their absolute safety, or their safety relative to existing treatments for a given condition. In the wake of the Vioxx recall, there were widespread calls by major newspapers, medical journals, consumer advocacy organizations, lawmakers, and FDA officials<ref name="Graham">{{cite web |url=http://www.finance.senate.gov/imo/media/doc/111804dgtest.pdf |title=David Graham's 2004 testimony to Congress |access-date=August 30, 2012 |archive-date=September 25, 2012 |archive-url=https://web.archive.org/web/20120925094651/http://www.finance.senate.gov/imo/media/doc/111804dgtest.pdf |url-status=live}}&nbsp;{{small|(28.3&nbsp;KB)}} Retrieved August 30, 2012.</ref> for reforms in the FDA's procedures for pre- and post-market drug safety regulation.

In 2006, a [[United States congressional committee|Congressional committee]] was appointed by the [[Institute of Medicine]] to review pharmaceutical safety regulation in the U.S. and to issue recommendations for improvements. The committee was composed of 16 experts, including leaders in clinical medicine medical research, economics, [[biostatistics]], law, public policy, public health, and the allied health professions, as well as current and former executives from the [[drug company|pharmaceutical]], hospital, and [[health insurance]] industries. The authors found major deficiencies in the current FDA system for ensuring the safety of drugs on the American market. Overall, the authors called for an increase in the regulatory powers, funding, and independence of the FDA.<ref name = "Henderson_2006">{{Cite web | vauthors = Henderson D |title=Panel: FDA needs more power, funds |work=[[The Boston Globe]] |date=September 23, 2006 | url = http://www.boston.com/business/healthcare/articles/2006/09/23/panel_fda_needs_more_power_funds/ | archive-url = https://web.archive.org/web/20121023223500/http://www.boston.com/business/healthcare/articles/2006/09/23/panel_fda_needs_more_power_funds/ | archive-date = October 23, 2012 }}</ref><ref>{{cite book | chapter-url = http://www.nap.edu/openbook.php?record_id=11750&page=205 | publisher = Books.nap.edu | archive-url = https://web.archive.org/web/20121025132523/http://www.nap.edu/openbook.php?record_id=11750&page=205 | archive-date=October 25, 2012 | chapter = Executive Summary of the 2006 IOM Report | title = The Future of Drug Safety: Promoting and Protecting the Health of the Public | date = 2007 | doi = 10.17226/11750 | isbn = 978-0-309-10304-6 }}</ref> Some of the committee's recommendations were incorporated into drafts of the PDUFA IV amendment, which was signed into law as the [[Food and Drug Administration Amendments Act of 2007]].<ref>{{cite web |url=https://www.fda.gov/oc/initiatives/advance/fdaaa.html |title=Food and Drug Administration Amendments Act (FDAAA) of 2007 |publisher=Food and Drug Administration |access-date=March 14, 2015 |archive-date=May 25, 2009 |archive-url=https://web.archive.org/web/20090525082137/http://www.fda.gov/oc/initiatives/advance/fdaaa.html |url-status=live}}</ref>

As of 2011, Risk Minimization Action Plans (RiskMAPS) have been created to ensure risks of a drug never outweigh the benefits of that drug within the post-marketing period. This program requires that manufacturers design and implement periodic assessments of their programs' effectiveness. The Risk Minimization Action Plans are set in place depending on the overall level of risk a prescription drug is likely to pose to the public.<ref>{{cite journal | vauthors = Qato DM, Alexander GC | title = Improving the Food and Drug Administration's mandate to ensure postmarketing drug safety | journal = JAMA | volume = 306 | issue = 14 | pages = 1595–1596 | date = October 2011 | pmid = 21990303 | doi = 10.1001/jama.2011.1457 }}</ref>

===Pediatric drug testing===
Prior to the 1990s, only 20% of all drugs prescribed for children in the United States were tested for safety or efficacy in a pediatric population.<ref>{{cite journal | vauthors = Temeck J |title=Pediatric Product Development in the U.S. |journal=FDA Seminar, Copenhagen |date=November 2010}}</ref> This became a major concern of [[pediatrician]]s as evidence accumulated that the physiological response of children to many drugs differed significantly from those drugs' effects on adults. Children react differently to the drugs because of many reasons, including size, weight, etc. There were several reasons that few medical trials were done with children. For many drugs, children represented such a small proportion of the potential market, that drug manufacturers did not see such testing as cost-effective.<ref name = "PedReg"/>

Also, the belief that children are ethically restricted in their ability to give [[informed consent]] brought increased governmental and institutional hurdles to approval of these clinical trials, and greater concerns about [[legal liability]]. Thus, for decades, most medicines prescribed to children in the U.S. were done so in a non-FDA-approved, "off-label" manner, with dosages "extrapolated" from adult data through body weight and body-surface-area calculations.<ref name = "PedReg"/>

In an initial FDA attempt to address this issue they produced the 1994 FDA Final Rule on Pediatric Labeling and Extrapolation, which allowed manufacturers to add pediatric labeling information, but required drugs that had not been tested for pediatric safety and efficacy to bear a disclaimer to that effect. However, this rule failed to motivate many drug companies to conduct additional pediatric drug trials. In 1997, the FDA proposed a rule to require pediatric drug trials from the sponsors of [[New Drug Application]]s. However, this new rule was successfully preempted in federal court as exceeding the FDA's statutory authority.<ref name="PedReg">{{Cite journal |author=Politis P |year=2005 |title=Transition From the Carrot to the Stick: The Evolution of Pharmaceutical Regulations Concerning Pediatric Drug Testing |journal=Widener Law Review |volume=12 |page=271}}</ref>

While this debate was unfolding, Congress used the [[Food and Drug Administration Modernization Act|Food and Drug Administration Modernization Act of 1997]] to pass incentives that gave pharmaceutical manufacturers a six-month patent term extension on new drugs submitted with pediatric trial data. The [[Best Pharmaceuticals for Children Act|Best Pharmaceuticals for Children Act of 2007]] reauthorized these provisions and allowed the FDA to request [[National Institutes of Health|NIH]]-sponsored testing for pediatric drug testing, although these requests are subject to NIH funding constraints. In the Pediatric Research Equity Act of 2003, Congress codified the FDA's authority to mandate manufacturer-sponsored pediatric drug trials for certain drugs as a "last resort" if incentives and publicly funded mechanisms proved inadequate.<ref name="PedReg"/>

===Priority review voucher (PRV)===
The [[priority review voucher]] is a provision of the [[Food and Drug Administration Amendments Act of 2007]], which awards a transferable "priority review voucher" to any company that obtains approval for a treatment for a [[neglected tropical diseases]]. The system was first proposed by [[Duke University]] faculty David Ridley, Henry Grabowski, and Jeffrey Moe in their 2006 ''[[Health Affairs]]'' paper: "Developing Drugs for Developing Countries".<ref name=Ridley06>{{cite journal | vauthors = Ridley DB, Grabowski HG, Moe JL | title = Developing drugs for developing countries | journal = Health Affairs | volume = 25 | issue = 2 | pages = 313–324 | year = 2006 | pmid = 16522573 | doi = 10.1377/hlthaff.25.2.313 | hdl-access = free | doi-access = free | hdl = 10161/7017 }}</ref> President Obama signed into law the [[Food and Drug Administration Safety and Innovation Act|Food and Drug Administration Safety and Innovation Act of 2012]], which extended the authorization until 2017.<ref name="PLAW_2012">{{cite web |url=http://www.gpo.gov/fdsys/pkg/PLAW-112publ144/pdf/PLAW-112publ144.pdf |title=Section 529 Rare Pediatric Disease Priority Review Voucher Incentive Program, Public Law 112-144 |publisher=Public Law |date=July 9, 2012 |access-date=November 19, 2015 |archive-date=March 6, 2016 |archive-url=https://web.archive.org/web/20160306214504/https://www.gpo.gov/fdsys/pkg/PLAW-112publ144/pdf/PLAW-112publ144.pdf |url-status=live}}</ref>

===Rules for generic biologics===
Since the 1990s, many successful new drugs for the treatment of cancer, [[autoimmunity|autoimmune diseases]], and other conditions have been [[protein]]-based [[biologic medical product|biotechnology drugs]], regulated by the [[Center for Biologics Evaluation and Research]]. Many of these drugs are extremely expensive; for example, the anti-cancer drug [[Avastin]] costs $55,000 for a year of treatment,<ref>{{Cite web |title=The Avastin Paradox |url=https://www.technologyreview.com/2009/07/13/30529/the-avastin-paradox/ |access-date=January 6, 2022 |website=MIT Technology Review |language=en |archive-date=January 6, 2022 |archive-url=https://web.archive.org/web/20220106123457/https://www.technologyreview.com/2009/07/13/30529/the-avastin-paradox/ |url-status=live }}</ref> while the [[enzyme replacement therapy]] drug [[Imiglucerase|Cerezyme]] costs $200,000 per year, and must be taken by [[Gaucher's disease]] patients for life.<ref name="govtrack.us">{{cite web |url=https://www.govtrack.us/congress/bills/110/hr1038 |title=To amend the Public Health Service Act to provide for the licensing of comparable and interchangeable biological products, and for other purposes. (2007; 110th Congress H.R. 1038) – GovTrack.us |work=GovTrack.us |access-date=March 14, 2015 |archive-date=January 12, 2015 |archive-url=https://web.archive.org/web/20150112032213/https://www.govtrack.us/congress/bills/110/hr1038 |url-status=live}}</ref>

Biotechnology drugs do not have the simple, readily verifiable chemical structures of conventional drugs, and are produced through complex, often proprietary, techniques, such as transgenic mammalian cell cultures. Because of these complexities, the 1984 [[Drug Price Competition and Patent Term Restoration Act|Hatch-Waxman Act]] did not include biologics in the [[Abbreviated New Drug Application]] (ANDA) process. This precluded the possibility of generic drug competition for biotechnology drugs. In February 2007, identical bills were introduced into the House to create an ANDA process for the approval of generic biologics, but were not passed.<ref name="govtrack.us"/>

===Mobile medical applications===
In 2013, a guidance was issued to regulate [[mobile medical apps|mobile medical applications]] and protect users from their unintended use. This guidance distinguishes the apps subjected to regulation based on the marketing claims of the apps.<ref>{{cite web |url=https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ConnectedHealth/MobileMedicalApplications/ucm255978.htm |title=Mobile Medical Applications |publisher=Food and Drug Administration |access-date=March 14, 2015 |archive-date=September 4, 2015 |archive-url=https://web.archive.org/web/20150904095950/http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ConnectedHealth/MobileMedicalApplications/ucm255978.htm |url-status=live}}</ref> Incorporation of the guidelines during the development phase of these apps has been proposed for expedited market entry and clearance.<ref>{{cite journal | vauthors = Yetisen AK, Martinez-Hurtado JL, da Cruz Vasconcellos F, Simsekler MC, Akram MS, Lowe CR | title = The regulation of mobile medical applications | journal = Lab on a Chip | volume = 14 | issue = 5 | pages = 833–840 | date = March 2014 | pmid = 24425070 | doi = 10.1039/C3LC51235E }}</ref>

===Electronic Submissions Gateway (ESG)===

To standardize, automate and streamline the flow of regulatory data, FDA introduced an Electronic Submissions Gateway (ESG) in 2006. This gateway allows reporting organizations to send regulatory submissions to different centers over the internet, packaged in a center-specific format and enveloped as a GNU-compatible .tar.gz file, through either a FDA-specific WebTrader application<ref>{{cite web |title=Setting up a WebTrader Account Checklist |url=https://www.fda.gov/industry/create-esg-account/setting-webtrader-account-checklist | publisher = U.S. Food and Drug Administ ration|date=May 12, 2023 }}</ref> or via a more generic B2B communication protocol called AS2 (Applicability Statement 2).<ref>{{cite web |title=AS2 Protocol |url=https://aayutechnologies.com/docs/as2/as2-protocol/ |website=Aayu Technologies}}</ref>

For WebTrader, which is recommended for manual, small-volume submissions, users would typically install a client application<ref>{{cite web |title=Food and Drug Administration |url=https://www.fda.gov/media/156910/download?attachment | publisher = U.S. Food and Drug Administ ration}}</ref> on their computers and upload the package through it to FDA server. In AS2, which is recommended for automated or high-volume submissions, users can use any standard AS2 software to transmit the package to FDA by including additional routing details on top of standard AS2, in the form of custom HTTP request headers.<ref>{{cite web |title=ESG Appendix F: AS2 Header Attributes |url=https://www.fda.gov/industry/about-esg/esg-appendix-f-as2-header-attributes | publisher = U.S. Food and Drug Administ ration|date=June 10, 2024 }}</ref>