en focused on antibiotic therapies is approach has been referred to a - PDF document

1 en focused on antibiotic thera-pies. "is
en focused on antibiotic thera-pies. "is approach has been referred to as limited population antibacterial drug (LPAD), or alternatively, as special medical use (SMU). "e concept is that for certain subsets of diseases (e.g., with multidrug-resistant microbial

2 infections) a very lim-ited clinical dev
infections) a very lim-ited clinical development program that recognizes the many in vitro and in vivo modeling priors associated with antibacterial drugs, possibly bolstered by a study or studies in drug-sensitive infections, would lead to a special approval.

3 A product approved by SMU/LPAD would be
A product approved by SMU/LPAD would be highlighted by a logo informing pre-scribers and patients of the limited nature of the development program. For antibiotics, there would be an expectation of good antibiotic stewardship.5 "e program would be voluntary for

4 sponsors, and no actual restrictions on
sponsors, and no actual restrictions on the practice of medicine would be needed. "is concept was explored by the FDA in a public meeting in February 2013 and has been discussed widely in other settings a#er it was endorsed in a report on drug devel-opment fro

5 m the PresidentÕs Council of Advisors on
m the PresidentÕs Council of Advisors on Science and Technology.6 Legislation supporting SMU/LPAD was intro-duced in Congress in December 2013.It is important to point out that early-access pathways in the United States are not mutually exclusive and may be lay

6 ered if the need and/or data warrant. Fo
ered if the need and/or data warrant. For instance, a fast-track desig-nation can be accompanied by a priority review, although this is not guaranteed. In addition, medicines developed under AA may or may not have a fast-track or breakthrough designation and ma

7 y or may not receive a priority review.E
y or may not receive a priority review.Existing early-access pathways at the EMAConditional marketing authorization (CMA), introduced in 2005, is similar to the FDAÕs AA. CMA is restricted to seri-ously debilitating and life-threatening conditions. "e mar-ketin

8 g authorization is valid for 1 year a#er
g authorization is valid for 1 year a#er it is granted but is renewable; CMA comes with the condition that the sponsor will initiate, or, preferably, continue studies in order to reduce uncer-tainty about bene!ts and risks and enable its conversion to a full m

9 arketing authorization. Multiple conditi
arketing authorization. Multiple conditions need to be met in order for a CMA to be granted, including that the medicine is meant to treat a serious and/or life-threatening condition, is for emergency use, or treats an orphan condition. In addition, the prelimi

10 nary bene!tÐrisk estimate must be positi
nary bene!tÐrisk estimate must be positive, the medicine must meet an unmet medical need, and there has to be a high likelihood that relevant postauthorization trials in the approved indication will be successful and/or have been initiated.Approval under except

11 ional circumstances is reserved for situ
ional circumstances is reserved for situa-tions in which the sponsor cannot, for practical or ethical reasons, conduct informative, well-controlled clinical trials resulting in comprehensive clinical evidence; for example, when the indica-tion is extremely rare

12 (ultra-orphan), the present state of sc
(ultra-orphan), the present state of scienti!c knowledge precludes robust data collection, or data collection would be contrary to medical ethics. Accelerated assessment, introduced in 2005, may be granted to a marketing application for medicines that are of m

13 ajor public health interest, particu-lar
ajor public health interest, particu-larly those representing therapeutic innovations. Accelerated assessment is granted prior to the initiation of the review of an application. It is similar to Òpriority reviewÓ in the United States. "e initial review, resulti

14 ng in a !rst list of questions, follows
ng in a !rst list of questions, follows the standard assessment timetable (120 days). If the application still ful!lls the requirements for accelerated assessment and no major issues remain, an accelerated timetable is communicated, leading to the Committee for

15 Medicinal Products for Human Use opinio
Medicinal Products for Human Use opinion. Generally, the goal is to !nalize the assessment within 150 days rather than the standard 210 days. Because no major issues should remain at Day 120, a rapid response is expected from the sponsor. If this is not the ca

16 se, the standard timetable applies. "is
se, the standard timetable applies. "is pathway has very rarely been used. R 5 | Nwww.nature.com/cptnature publishing groupSTATE ART!ere is consensus among stakeholdersÑpatients, providers, academic researchers, regulators, health technology assess-men

17 t (HTA) bodies/payers (who may or may no
t (HTA) bodies/payers (who may or may not be in the same organizations depending on the region/country), and the pharmaceutical industryÑagreement that an important goal of todayÕs health-care system is to provide patients timely access to new and meaningfully

18 better medicines at reasonable costs. Ho
better medicines at reasonable costs. However, the current ÒsiloedÓ system of biomedical innova-tion increases development costs, time, and risks. !e timeli-ness of access is largely controlled by three stakeholder groups: the pharmaceutical and biotechnology c

19 ompanies, who are responsible for develo
ompanies, who are responsible for developing new medicines; the regulators, who are responsible for the review of safety, e"cacy, and quality data and subsequent regulatory decision making, thus making the new medicine available to the marketplace; and the HTA

20 bod-ies/payers, who are responsible for
bod-ies/payers, who are responsible for assessing and/or paying the orts, are discussed here. !e e nology industries to build and sustain innovative pipelines of new medicines are well reported elsewhere.Since the late 1980s and early 1990s, regulators and HTA

21 bod-ies/payers around the world have be
bod-ies/payers around the world have been actively pursuing vari-ous approaches to making important medicines available to the patients who need them in a timely manner, recognizing that patients and providers are willing to tolerate greater risks, espe-cially

22 risks of the unknown about medicines, w
risks of the unknown about medicines, when the morbid-ity of the disease is signi#cant or when the disease is potentially life-threatening. !e development of new approaches to provide timely access has continued since their earliest introduction and continues

23 today. !ere are currently a number of ap
today. !ere are currently a number of approaches/pathways that have been implemented by regulators and HTA bodies/payers in various regions, and this has resulted in some c medicine and which might yield the greatest bene#ts and/or unacceptable risks. For this

24 reason, we have compared and contrasted
reason, we have compared and contrasted the existing, new, and emerging pathways, strategies, and approaches that have been or are being implemented by regulatory agencies and/or HTA bodies/payer organizations. In addition, we have employed Òuse metricsÓ to ev

25 aluate the success of the e$orts, to dat
aluate the success of the e$orts, to date, and propose recom-mendations for possible future improvements.REGULATORY EARLY!ACCESS PATHWAYS!e approaches and processes used by drug regulatory agencies are similar in most regions. However, we have included only er

26 apeutics10.1038/clpt.2014.145State of t
apeutics10.1038/clpt.2014.145State of the Art13August201496530April20142July2014There is broad agreement among health-care stakeholders that more must be done to ensure that patients have timely access to new and innovative medicines. Assuming that industry w

27 ill continue to develop such medicines a
ill continue to develop such medicines at a sustainable rate, regulators and payers become the gatekeepers. Regulators, starting in the late 1980s/early 1990s, and, more recently, payers have implemented a variety of early-access pathways or initiatives, and th

28 is practice is continuing even today. Th
is practice is continuing even today. This article describes the specific approaches that have been taken in four economically developed regions, reviews their success rates, and suggests possible new directions.1Center for Biomedical Innovation, Massachusetts

29 Institute of Technology, Cambridge, Mass
Institute of Technology, Cambridge, Massachusetts, USA; 2Institut National dÕExcellence en SantŽ et en Services Longson7, E!Pezalla8, T Tunis10, JWoodcock11 and G!Hirsch1OpenCLINICAL PHOLOGY & THERAPEUTICS | VOLUME 96 NUMBER 5 | N !"#$%&$'($)*&+,)$-%./)-(($00)

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36 4-.*#")'!.*+C.)$':-!!%"'D14-"%&#x -25;&#
4-.*#")'!.*+C.)$':-!!%"'D14-"%&#x -25;&#x 000;'2#/$1$*'#D'9."1#-$'.!!"#.2+%$'*#'(../2%'*+%'8#8%/*'#D'8."B%*'.-*+#"1=.*1#/'C1*+'.'2%"*.1/'%9%'#D'B/#C%&4%'.(#-*'*+%'!"#&-2*;' )&%&*)( and effectiveness and apply the MEAsÕ procedures 107Chapter 13: Cancer Drugs Reg

37 ister of the Italian Medicines Agency an
ister of the Italian Medicines Agency and Its Use in Risk ManagementIntroductionThe Italian National Health System, in its efforts to guar-antee health insurance for Italian citizens on a universal basis, is more and more engaged with the challenges of new phar

38 maceuticals, which can bring high prices
maceuticals, which can bring high prices along has been involved for some time in creating innovative support projects to assist regulatory activity, with the intent of both improving the ef!cacy and ef!-ciency of the agencyÕs analysis and regulatory activiti

39 es and closely monitoring clinical activ
es and closely monitoring clinical activity to obtain information relevant to strategic planning to improve the National Health Service.Within normal clinical practice, speci!cally in hospitals, the prescriber should take into account the parameters of the ther

40 apeutic drugÕs indication, the actual be
apeutic drugÕs indication, the actual bene!t the patient should gain in comparison to the trials, the potential and actual risk of adverse reactions, drug interactions and the cost of the therapy (growing exponentially, especially for innovative drugs). Region