A02-Portable-Oxygen-Carrier-COGM-RFI-Attach4-Technology-Readiness-Levels.pdf

E-3

Note: Medical-related items require Technology Readiness Level (TRL) definitions and descriptions that are appropriate to the technologies upon which they are based and that account for the statues and regulations that govern their development and use. In recog-nition of these factors, the United States Army Medical Research and Materiel Command (USAMRMC) took the initiative to establish appropriate definitions, descriptions, and processes in the context of military medical research and development (R&D) and Food and Drug administration (FDA) statutory and regulatory requirements. This appendix provides the results of their effort.

E.1 Background

Department of Defense (DoD) policy mandates the use of U.S. FDA-approved products for force health protection,1 and the USAMRMC has always adhered to the regulatory requirements of the FDA for its studies of drugs, biologics, and devices in humans. To ensure compliance with the clinical phases of the FDA-regulated process and to reduce technological risk, the USAMRMC developed and recently updated their gen-eral guidelines for assigning TRLs to drug, vaccine, and medical device development programs.2 These guidelines are not considered absolutes, and characterization of activi-ties associated with TRLs can and does vary at times.

The science and technology (S&T) and acquisition program managers (PMs) work together in exercising discretion in the selection, progression, and timing of specific activities to be accomplished in the attainment of particular TRLs. Such flexibility and tailoring are needed to align the TRL decision criteria appropriately with the maturation and risk characteristics of a particular technology, including consideration of the associ-ated investment strategy and transition procedures that may vary among PMs.

1 For example, Department of Defense Directive (DoDD) 6200.2, Use of Investigational New Drugs for Force Health Protection, August 1, 2000, or Health Affairs Policy 95-011, Tri-Service Pharmacy Pol-icy Guidance, July 26, 1995.

2 Biomedical Technology Readiness Levels (TRLs), prepared for the Commander, U.S. Army Medical Research and Materiel Command, under Contract DAMD17-98-D-0022, Science Applications International Corporation, 3 June 2003.

E-4

When transitioning from technology development to product development, the risks are greater if the TRL of a Critical Technology Element (CTE) is low. For medical technologies, risk reduction is not linear across TRLs. The rate of risk reduction remains very low until very late. Historically, FDA-regulated products, such as vaccines, do not achieve significant risk reduction (i.e., greater than 50%) until completion of Phase 3 clinical trials and approval of a biologics license application by the FDA (TRL 8). Indus-try’s experience is that only one in four vaccines going into Phase 3 trials is licensed.

Similarly, whereas technology maturation is commonly perceived as a sequential contin-uum of activities from basic research, through development, to production and deploy-ment, the evolution of the TRL for a biomedical CTE may not be sequential, especially in those cases where FDA anchors are undefined. In cases of success or failure, the incre-mental change in the level of technology readiness may be greater than a single TRL. For example, upon successful completion of a pivotal study, biomedical information readi-ness levels may move from TRL 3 or 4 to TRL 9.

Biomedical TRL descriptions provide a systematic way for the S&T community to assess and communicate to the Milestone Decision Authority (MDA) the maturity level of a particular technology or combination of technologies and the maturity neces-sary for successful product development. This appendix provides equivalent TRL descriptions applicable to biomedical technologies in four categories:

1. Pharmaceutical (i.e., drugs)

2. Pharmaceutical (i.e., biologics/vaccines)

3. Medical Devices

4. Medical Information Management/Information Technology (IM/IT) and

Medical Informatics.

The TRLs for the first three categories have been developed from the DoD’s generic definitions, the applicable FDA regulatory process, and industry practices and experience with its R&D processes (discovery through manufacturing, production, and marketing). The last category includes elements of formal regulatory processes and logi-cal events in deriving comparable levels of maturity. Wherever practical, the USAMRMC intends to use external anchors such as “FDA events” to define each TRL decision criterion. Furthermore, activities described as occurring between successive TRL decision criteria are intended to exemplify the kinds of activities that routinely take place when maturation is sequential and stepwise. However, these examples are neither mandatory nor all inclusive.

Figure E-1 and Table E-1 build upon this work by providing examples of sup-porting information and documentation required to support the assignment of TRLs as the program progresses.

The proponent for this document is the Deputy for Research and Development:

Commander, U.S. Army Medical Research and Materiel Command, ATTN:

MCMR-ZA, 504 Scott Street, Fort Detrick, MD 21702-5012.

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d e vi ce d e si g n va lid a te d a nd fi na l pr o to ty pe s p ro du ce d

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pr o to ty p e in cl in ic a l t ria ls

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S o lu ti o n s fo r M ili ta ry P ro b le m s N o ve l C o n ce p ts a n d

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T e c h n o lo g ie s

E-5

E-6

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G en e ra l N o te f o r

T a b le

E -1

T he N

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N o te s th a t a re li st e d a t t he e nd o f T ab le E

-1

T ab le E

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R L s fo r M ed ic al R e se a rc h , D e ve lo p m en t, T es t, a n d E va lu a ti o n

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A c q u is it io n

G u id eb o o k3 T

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S A

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L

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U S

A M

R M

C E q u iv al en t

T R

L D es cr ip ti o

P h ar m ac e u ti ca l

(D ru g

s) N

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M ed ic al I

M

/IT

e d ic a l I n fo rm a ti cs

Lo w e st le ve l o f t ec hn ol o gy r e ad in es s.

S ci e n tif ic re se a rc h b e gi n s to b e tr an sl at e d in to a p p lie a rc h a n d d e ve lo p-m en t.

E xa m pl es m ig ht in cl ud e p a pe r st u d ie of te ch no lo gy ’s b as pr op er tie s.

L ow e st le ve l o f t e ch n o lo g y re ad in es s.

M a in te n an ce o f sc ie nt ifi c aw ar en es s a nd g e ne ra tio sc ie nt ifi c an d b io en g in e er in g kn o w le d g e b as e

S ci e nt ifi c fin di n g s ar e r e vi e w e d an d as se ss ed a f ou nd at io n fo r ch a ra ct e riz in g n ch n ol o gi es

L ow e st le ve l o f t e ch n o lo g y re ad in es s.

M a in te n an ce o f sc ie nt ifi c aw ar en es s a nd g e ne ra tio nt ifi c an d b io en g in e er in g kn o w le d ge b as e

S ci e nt ifi c fin di n g s ar e r e vi e w e d an d as se a f ou nd at io n fo r ch a ra ct e riz in g n n ol o gi es

L ow e st le ve l o f t e ch n o lo g y re ad in es s.

M a in te n an ce o f sc ie nt ifi c aw ar en es s a nd g e ne ra tio nt ifi c an d b io en g in e er in g kn o w le d ge b as e

S ci e nt ifi c fin di n g s ar e r e vi e w e d an d as se a f ou nd at io n fo r ch a ra ct e riz in g n n ol o gi es

H a rd w a re

/s o ft w a re

H

W /S

W sy st e m te ch n ol o gy e xp lo d.

B ic t he or ie s a pp lie d t o

IM

/I fie ld s ug g es tin g pr om is e.

L

D ec is io n C ri te ri o n

S ci en tif ic li te ra tu vi e w s an d in iti a l m a rk e t s ur ve ys a re in iti at e d a nd a ss e ss e d.

P ot e n tia l s ci en tif ic a p pl ic a tio to ef in ed p ro b le m s is a rt ic u la

L

D ec is io n C ri te ri o n

S ci en tif ic li te ra e w s an d in iti a l m a rk e t s ur ve ys a re in iti at e d a nd a ss e ss e d.

P ot e n tia l s ci en tif ic a p pl ic a tio in ed p ro b le m s is a rt ic u la te d.

T R

L

D ec is io n C ri te ri o n

S ci en tif ic li te ra e w s an d in iti a l m a rk e t s ur ve ys a re in iti at e d a nd a ss e ss e d.

P ot e n tia l s ci en tif ic a p pl ic a tio in ed p ro b le m s is a rt ic u la

L

D ec is io n C ri te ri o n

Id e nt ifi ca tio n o f t he p o te nt ia l m e d ic a l s ol u tio n t o m is si o n n ee d.

M ed ic a l I nf o rm a tic s da ta nd k no w le d ge r ep re se nt at su e s a re d ef in e d.

S u p p o rt in g

In fo rm at p p o rt in g I n fo rm at p p o rt in g In fo rm at vi e w s of o pe n

, p u bl is he d s ci e nt ifi c lit er a co nc e rn in g ba si c pr in ci p le s.

F in d in g s fr om m a r-ke t s u rv e ys o f t he o p en li te ra tu re

N o te

P ri va te ly f un d e d re se a rc h fin di n g s o r m a rk e t s u rv ey s a re p ro p rie ta ry a n d ra re ly a va il-a bl e t o th e pu b lic

R e vi e w s of o pe n

, p u bl is he d s ci e nt ifi c lit er a e rn in g ba si c pr in ci p le s.

F in d in g s fr om m a r-ke t s u rv e ys o f th e o pe n lit e ra tu

N te

P ri va te ly f un d e d re se a rc h fin di n g s o r m a rk e t s u rv ey s a re p ro p rie ta ry a n d ra re ly a va il-a bl e t o th e pu b lic

R e vi e w s of o pe n

, p u bl is he d s ci e nt ifi c lit er a e rn in g ba si c pr in ci p le s.

F in d in g s fr om m a r-ke t s u rv e ys o f t he o p en li te ra tu re

N o te

P ri va te ly f un d e d re se a rc h fin di n g s o r m a rk e t s u rv ey s a re p ro p rie ta ry a n d ra re ly a va il-a bl e t o th e pu b lic

T he D ef en se A cq ui si tio n G ui de bo ok in r ev is io

n) c on ta in s no n-m an da to ry g ui da nc e on b es t p ra ct ic es

, l es so ns le ar ne d, a nd e xp ec ta tio ns

E-7 ab le E

-1 . P ro p o s ed T

R L s f o r

M ed ic a l R D

T

E

C o n ti n u ed

T R

L

N A

S A

/D e fe n s e

A cq u is it io n G u id e b o o k T

R L

D e fi n it io n

T ec hn o lo gy c on ce pt a nd

/o r a pp lic a tio n fo rm ul a te d

N A

S A

D ef en se A c q u is it id eb o o k T

R L

D es cr ip ti

A M

R M

C E q u iv al en t

T R

L D es cr ip ti o ar m ac e u ti g

s) N

1, N

P h ar m ac e u ti lo g ic s

, V ac c in es )N

1, N

M ed ic al D ev ic e sN

3, N

M ed ic al

IM

/I ic al

I n fo rm at

In ve n tio n b eg in s.

O ba si c pr in ci p le s ar e o bs er ve d, p ra ct al pp lic at io ns c a n b e in ve nt e d.

A p p lic a tio n s a re s pe cu la tiv e, th er e m a y b e n o p ro o f o r d et a ile d a n al ys or t th e as su m p tio ns

E xa m pl es a re li m ite d t na ly tic s tu d n se in te lle ct u al f oc u s o n th e p ro b le m ith g er at io n o f sc ie nt ifi c

“p ap e r st ud ie s” t at e w a n d g e ne ra te r es e ar ch id e as hy p o th e se s, a n d e xp er im e n ta l d e si gn s fo r a dd re ss in g th e r e la te d s ci en tif ic is su es

In te n se in te lle ct u al f oc u s o n th e p ro b le m er at io n o f sc ie nt ifi c

“p ap e r st ud ie s” t e w a n d ge ne ra te r es e ar ch id e as hy p o th e se s, a n d e xp er im e n ta l d e si gn s fo r a dd re ss in g th e r e la te d s ci en tif ic is su es

In te n se in te lle ct u al f oc u s o n th e p ro b le m er at io n o f sc ie nt ifi c

“p ap e r st ud ie s” t e w a n d ge ne ra te r es e ar ch id e as hy p o th e se s, a n d e xp er im e n ta l d e si gn s fo r a dd re ss in g th e r e la te d s ci en tif ic is su es

H W

/S W s ys te m in ve n tio n b eg in s.

O ve ra ll sy st e m c o n ce pt s ar e d oc u m e nt e d b y flo w ch a rt in g o r ot he r sy st em d es cr ip tiv e te ch n iq ue s.

T R

L

D ec is io n C ri te ri o n

H yp ot h e si s( e s) ge ne ra te d.

R e se a rc h p la ns a nd /o r p ro to co ls ev el o pe d, p e e r re vi e w e d , a nd a p pr ov ed

T R

L

D ec is io n C ri te ri o n

H yp ot h e si s( e ra te d.

R e se a rc h p la ns a nd /o r p ro to co ls el o pe d, p ee r re vi e w ed , a nd a p p ro ve d

T R

L

D ec is io n C ri te ri o n

H yp ot h e si s( e ra te d.

R e se a rc h p la ns a nd /o r p ro to co ls el o pe d, p e e r re vi e w e d , a nd a p pr ov ed

T R

L

D ec is io n C ri te ri o n

Id e nt ifi ca tio n o f t he p o te nt ia l m e d ic a l s ol u tio n t o m is si o n n ee d.

M ed ic a l I nf o rm a tic s da k no w le d ge r ep re se nt at e s a re d ef in e d.

S u p p o rt in g

I n fo rm a ti o n

S u p p o rt in g

I n fo rm a ti o n

S u p p o rt in g

I n fo rm a ti o n

F oc us ed li te ra tu re r e vi e w s a re c o nd uc te d nt ifi c di sc us si on s a re h e ld to g e n e ra ar ch p la n s a nd s tu di es t h at id en tif y p ot e n tia l ta rg et s of o p p o rt u ni ty f or t he ra pe u tic in te rv e n tio n a n d t o fa ci lit at e s tr at e g ic p la nn in g.

S u p-p or tin g a na ly se s pr o vi d e s ci e nt ifi c in fo rm a tio n a nd d a ta f or d e ve lo pi n g r es ea rc h pr o po sa ls fo r fil lin g in d a ta g ap s a n d id en tif yi n g ca nd id e pt s a nd

/o r th er ap eu tic d ru gs

D oc u m e nt b y p e er

-r e vi e w e d ap pr ov ed p ro to co l(s or a rc h p la n (s oc us ed li te ra tu re r e vi e w s a re c o nd uc te d nt ifi c di sc us si on s a re h e ld to g e n e ar ch p la n s a nd s tu di es t h at id en tif y p ot e n tia l ta rg et s of o p p o rt u ni ty f or t he ra pe u tic in te rv e n tio n a n d t o fa ci lit at e s tr at e g ic p la nn in g.

S u p-p or tin g a na ly se s pr o vi d e s ci e nt ifi c in fo rm a tio n a nd d a ta f or d e ve lo pi n g r es ea rc h pr o po sa ls fo r fil lin g in d a ta g ap s a n d id en tif yi n g ca nd id e pt s a nd

/o r th er ap eu tic d ru gs

D oc u m e p e er

-r e vi e w e d ap pr ov ed p ro to co l(s a rc h p la n us ed li te ra tu re r e vi e w s a re c o nd uc te d nt ifi c di sc us si on s a re h e ld to g e n e ar ch p la n s a nd s tu di es t h at id en tif y p ot e n tia l ta rg et s of o p p o rt u ni ty f or t he ra pe u tic in te rv e n tio n a n d t o fa ci lit at e s tr at e g ic p la nn in g.

S u p-p or tin g a na ly se s pr o vi d e s ci e nt ifi c in fo rm a tio n a nd d a ta f or d e ve lo pi n g r es ea rc h pr o po sa ls fo r fil lin g in d a ta g ap s a n d id en tif yi n g ca nd id e pt s a nd

/o r de vi ce s.

D oc u m e nt e d b y p e e r-re vi e w ed a p pr ov ed p ro to co l(s or r e se ar p la n

E-8 le E

-1 . P ro p o s ed T

R L s f o r

M ed ic a l R D

T

E

C o n ti n u ed

T R

L

N A

S A

/D e fe n s e

A cq u is it io n G u id e b o o k T

R L

D e fi n it io n

A na ly tic a l a nd e xp er im e nt a l c ri tic a l f un ct io n an d /o r ch ar ac te ri st ic p ro of -o f-co nc ep t

N A

S A

D ef en se A c q u is it id eb o o k T

R L

D es cr ip ti

A M

R M

C E q u iv al en t

T R

L D es cr ip ti o ar m ac e u ti g

s) N

1, N

P h ar m ac e u ti lo g ic s

, V ac c in es )N

1, N

M ed ic al D ev ic e sN

3, N

M ed ic al

IM

/I ic al

I n fo rm at

A ct iv e re se a rc h de lo p m en t is in iti a hi s in cl u de s a n a ly tic st ud ie s a n d la bo ra d ie s to p hy si lly lid at e a n al yt ic a l p re d ic tio ns o f s ep ar le m en ts o f t he t ec h no l-og y.

E xa m p le s in cl p o n e nt s th a t a re ot ye in te g ra te d o r re pr e se n ta tiv e

B a si c re se a rc h d at a co lle ct io n, a nd a n a ly si s b eg in in o rd e r to t e st t h e h yp o th es is ex p lo lte rn at iv e c on ce pt s, a n d id en tif y a nd e va lu n o lo g ie s su p po rt in g d ru g d ev el o p m e nt

In iti al s yn th e si s o f co u n te rm e as u re c an d id a te (s a nd id en tif ic a tio n o f th ei r si te s a n d m ec ha ni sm s o f a ct io n.

In iti al c ha ra ct er iz a tio n o f c an d id at cl in ic al s tu d si c re se a rc h d at a co lle ct io n

, a nd a n a ly si s b eg in in o rd e r to te st h yp o th es is e xp lo re a lte r-n at iv e co n ce pt s, a nd id e nt ify a n d e va lu a te c rit i-ca l t e ch no lo gi es a nd c o m po ne n ts s u p p or tin id at e b io lo g ic

/v a cc in e co ns tr uc ts r e se a rc h a nd e ve nt u al d e ve lo p m e nt o f a c a nd id un te rm ea su re

A ge nt c ha lle ng e st u di e s ar e co nd uc te d to s up p o rt m od e ls b as ed o n pr e-su m e d ba ttl ef ie ld c on di tio ns

R es e ar ch -s ro ce ss in iti at io n an d e va lu a tio n is c o nd uc d, a re s tu di es to id en tif y si te (s a nd m ec ha n-is m (s o f a ct io n, p ot e n tia l c or re la te s of p ro te c-tio n fo r va cc in es an d in iti al p h ys ic al /c h em ic a l ch ar ac te riz a tio n o f c on st ru ct s.

B a si c re se a rc h d at a co lle ct io n

, a nd a n a ly si s b eg in in o rd e r to te st h yp o th es is e xp lo re a lte r-n at iv e co n ce pt s, a nd id e nt ify a n d ev al u at e co m p on en t t ec h no lo gi es

In iti al te st s of d es ig n co nc e pt a nd e va lu at io n of c a nd id a te

(s

S tu d y en dp oi nt s de fin ed

A n im al m o de ls if an y) p os ed . D es ig n v er ifi ca tio n cr iti ca l c o m p o-n en t s pe ci fic a tio n s, a n d te st s

(if a s ys te m c om p on en t o r n e ce ss a ry f or d e vi ce te st a nd e va lu a-tio n

(T

E

S ep ar at e e le m en ts o f

H W

/S W sy e m c o m p on e nt s ar e in ve s-tig at e d a nd d e ve lo p ed b ut n o t ye t in te g ra te d o r re p re se n ta tiv e

T R

L

D ec is io n C ri te ri o n

In iti a l p ro of

-o f-co nc ep t f o r ca nd id a te d ru g co ns tr uc ts is d em on st ra te d in a li m ite d n um be r of in v itr o an d in v iv o re se ar ch m o de ls

T R

L

D ec is io n C ri te ri o n

In iti a l p ro of

-o f-co nc e pt f or b io lo g ic /v a cc in e co ns tr uc ts is d em o ns tr at ed in a li m ite d n u m b e r of in v itr o an d in vi vo r es e ar ch m o de ls

T R

L

D ec is io n C ri te ri o n

In iti a l p ro of

-o f-co nc e pt f or d e vi ce c an di d at es is d em on st ra te d in a li m ite d n u m b er o f la bo ra to ry m od el s

(m ay u de a n im al s tu di e s)

T R

L

D ec is io n C ri te ri o n

M e d ic al I n fo rm at ic s da ta kn ow le d ge r ep re se nt a tio n sc he m a ar e m od el ed

S u p p o rt in g

In fo rm at p p o rt in g I n fo rm at p p o rt in g I n fo rm at cu m e nt a tio n of t he r es ul ts o f la b or at or y st ud ie s d e m on st ra te s p re lim in a ry p ro of

-o f-co nc e pt in in v itr o an d a ni m al s tu di e s.

D o cu m e nt a tio n of t he r es ul ts o f la b or at or y st ud ie s d e m on st ra te s p re lim in a ry p ro of -o f-co nc e pt w ith c an di da te b io lo g ic /v a cc in e co n st ru ct s in in v itr o an d a ni m a l s tu d ie s.

D o cu m e nt a tio n of t he r es ul ts o f la bo ra ie s d e m on st ra te s p re lim in a ry p ro of -o f-co nc e p t i n la b o ra to ry m od el

E-9 le E

-1 . P ro p o s ed T

R L s f o r

M ed ic a l R D

T

E

C o n ti n u ed

T R

L

N A

S A

/D e fe n s e

A cq u is it io n G u id e b o o k T

R L

D e fi n it io n

C o m po ne n t a nd

/o r br ea d bo a rd v al id a tio n in la bo ra to ry e nv iro nm en t

N A

S A

D ef en se A c q u is it id eb o o k T

R L

D es cr ip ti

A M

R M

C E q u iv al en t

T R

L D es cr ip ti o n s

P h ar m ac e u ti g

s) N

1, N

P h ar m ac e u ti lo g ic s

, V ac c in es )N

1, N

M ed ic al D ev ic e sN

3, N

M ed ic al

IM

/I ic al

I n fo rm at si c te ch n o lo gi ca l co m p on en ts a re in te g ra te d t o e st a b lis h th a t th ey w ill w or k to g et he r.

s is r e la tiv el y “l fid el ity co m p a re d to nt ua l s ys te m

E xa m p le s in cl u de in te g ra tio n o f “ a d ho c” h a rd w a la bo ra to ry

N o n- G o o d L ab or at o ry P ra ct ic e

(G

LP

la bo ra a rc h to r ef in e h yp o th es is a n d id e nt ify r el e va n t p ar am et ric d a ta r eq u ire d fo r te ch n ol o gi ca l a ss e ss m en t in a r ig or ou s (w o rs t c as

e) e xp e ri-m e n ta l d e si gn

E xp lo ra to ry s tu dy o f c an d id g s (e

.g f o rm ul at io n, r ou te

(s o f ad m in is tr at io n m e th o d o f sy nt h es is p hy si ca l/c he m ic al p ro pe rt s, ta b ol ic fa te a n d e xc re tio n or e lim in at io n, os e ra ng in g)

C an di da te d ru gs a re e va lu at ni m al m o de l(s to id e n tif y an d as se ss p o te n tia l sa fe ty a n d to xi ci ty p ro b le m s, a d ve rs e e ve nt s, a e e ff ec ts

A ss a ys t o b e u se d d u rin g n on -c lin c lin ic al s tu d ie s in e va lu a tin g ca n di da te d gs id e nt ifi n- G

L P la bo ra to ry r es ea rc h to r ef in e h yp ot h e si s a nd id en tif y re le va n t p ar a m et ri c d at a r eq ui re d fo r te ch n o lo g ic a l a ss es sm en t i n a ri go ro us w e xp e rim en ta l d e si g n.

E xp lo ra to ry s tu dy o f cr iti ca l t e ch n o lo gi e s fo r ef fe ct iv e in te g ra tio n id at e b io lo g ic

/v ac ci n e co ns tr uc ts e

.g e n vi ro n m e nt al m ili eu pH , a d ju va n t, st ab ili ze rs a n d p re se rv a tiv e s, b u ffe rs an d so fo rt h r ou te th o ds o f ad m in is tr a tio n, p ro p o se d p ro d u ct n/ ur ifi ca tio n m et ho ds fu rt h er p h ys ic a l/c he m ac te riz at io n, m et a b ol ic f a te a n d e xc re tio n o r e lim in at io n, d os e r an g in g , a n d a ge nt c h al le ng e st ud ie s fo r p ro te ct io n)

C a nd id at e b io lo g ic /v ac ci n e co ns tr uc ts a re e va lu at e d in a ni m a l m o de l(s id tif y a n d a ss e ss s af et y an d to xi ci ty b io lo g ic a l ef fe ct s, a dv er se e ffe ct s, a nd s id e ef fe ct s.

A ss rr og a te m a rk e rs

, a nd e n dp o in ts to b e u se d d ur in g n o n-cl in ic al a n d c lin ic a l s tu di es t o e va lu at e a nd c ha ra ct e riz e c a n d id at e b io lo g ic

/v ac ci n e co n st ru ct s a re id en tif ie d

N o n- G

L P la bo ra to ry r es ea rc h to r ef in e h yp ot h e si s a nd id en tif y re le va n t p ar a m e tr ic d at a r eq ui re d fo r te ch n o lo g ic a l a ss es sm en t i n a ri go ro us w e xp e rim en ta l d e si g n.

E xp lo ra to ry s tu dy o f ca nd id at e d ev ic e (s sy st e m s

(e .g in iti a l s p ec ifi ca tio n o f d e vi ce

, s ys te m an d s u bs ys te m s)

. C an di d at e d ev ic es /s ys te m s a re e va lu a te d in la b or at

/o r a ni m a l m od e ls to id e nt ify a nd a ss es s p ot e nt ia l s af et y p ro bl e m s, a d ve rs e e ve n ts an d si d e e ff ec ts

P ro ce d u re s a n d m et ho d s to b e us in g n o n-cl in ic al a n d cl in ic a l s tu di lu a tin g c a nd id at e de vi ce s/ sy st em s tif ie d.

T h e d es ig n h is to ry f ile d es ig n r ev ie w a nd , w he n re qu ire d, a D ev ic e M a st e r

R ec

R a re in iti at ed t o su p po rt e ith er a

0(

k) 4 o r P re m a rk et A pp ro va l (

P M to ty p e pr od u ce d

H W

/S W s ys te m c om p o n en ts a re in te g ra te a b lis h th at th e p ie ce s w ill w o rk t og et h er

T r e la tiv el y

“l o w f id el ity co m p ar ed t o t he e ve n-tu a l s ys te m

T R

L

D e ci si o n

C ri te ri o n

P ro o f-of -c o nc ep t a sa fe ty o f ca n d id at e d ru g fo rm u la tio n( s) a re d e m o ns tr at ed in d e fin e d la b or a to ry /a ni m al m od el

L

D ec is io n C ri te ri o n

P ro of -o f-co n ce pt ty o f ca nd id at e b io lo g ic /v a cc in e c o n st ru ct s em on st ra te d in d ef in ed la b or at o ry

/a ni m a l m od el

(s

T R

L

D ec is io n C ri te ri o n

P ro of -o f-co n ce pt ty o f ca n d id at e d ev ic es /s ys te m s ar e d em o n st ra te d in d ef in e d la b or a to ry /a ni m a l m od

L

D ec is io n C ri te ri o n

M ed ic a l I n fo rm a t-ic s d at a a n d kn o w le d g e re pr es en ta tio n m o ls in st an tia te d re se n ta tiv e d a ta o r kn ow le d ge fr om a pp lic a-bl e d om a in

S u p p o rt in g

In fo rm at p p o rt in g I n fo rm at p p o rt in g I n fo rm a ti cu m e nt e d pr o of -o f-co n ce p t an d sa fe ty o f ca n d id a te d ru g fo rm ul a tio n s a re d e m on st ra te d b y re su lts o f f o rm u la tio n s tu d ie s, la b or a to ry t e ha rm ac ok in et ic s tu di e s, a n d s e le ct io n o f la bo ra to ry /a n im al m o d e ls

D o cu m e nt e d pr o of -o f-co n ce p t an d sa fe ty o f ca n d id a te b io lo gi cs /v a cc in es a re d e m o n st ra te d b y re su lts o f pr op os e d p ro d uc tio n /p u rif ic at io n m e th o ds la bo ra to ry t e st s, p h ar m oc ok in et ic s tu d s el ec tio n o f la b o ra to ry

/a n im al m o d el s.

R e vi e w er s co nf ir m p ro o f-of

-c o nc e pt a n d s af et y o f ca nd id at e d ev ic e s/ sy st e m s fr o m la bo ra to ry t es t re su lts la b or at or y/ an im al m o de ls a nd d o cu m en ta tio n o f t h e in iti al d e si g n h is to ry f ile , d e si e w an d, w he n re q u ir ed a

D M

R

T he d o cu m e n te d in iti a l d e si gn h is to ry f ile

, d es ig n r ev ie w an d, w he n re qu ire d, a D

M R s up p o rt e ith e

(k o r P

M A

A

(k is a p re m ar ke t n ot if ic at io n fo r m ed ic al d ev ic es

E-10 le E

-1 . P ro p o s ed T

R L s f o r

M ed ic a l R D

T

E

C o n ti n u ed

T R

L

N A

S A

/D e fe n s e

A cq u is it io n G u id e b o o k T

R L

D ef in it io n

C o m po ne n t a nd /o r br ea d bo ar d v a lid a tio n in a r el ev an t e nv iro nm en t

N A

S A

D ef en se A c q u is it id eb o o k T

R L

D es cr ip ti

A M

R M

C E q u iv al en t

T R

L D es cr ip ti o n s

P h ar m ac e u ti g

s) N

1, N

P h ar m ac e u ti lo g ic s

, V ac c in es )N

1, N

M ed ic al D ev ic e sN

3, N

M ed ic al

IM

/I ic al

I n fo rm at e lit y of b re ad b o ar d te ch n o lo gy in cr ea se s si g n ifi ca n tly

T he b n ol o gi ca l c om po n en ts a re in te g ra te d on a bl y re a lis or tin g el e m en ts s o th ey c an b e te st e d ul at ed e n vi ro nm e nt

E xa m pl es in cl ud e “h ig h fid el ity la b or at o ry in te gr at io n of c o m p on en ts

In te n se p e rio d o f no n-cl in ic a l a nd p re cl in ar ch s tu d ie s in vo lv in g p a ra m e tr ic d lle ct io n an d a n al ys is in w e ll-d e fin ed s ys te p ilo t lo ts o f ca n di d a te p ha rm ac e ut ic ls d uc ed a n d f u rt he r d ev el op m en t o f se le id at e( s)

R es u lts o f re se ar ch w ith p ilo t lo ts vi de b a si s fo r a m a nu fa ct ur in g p ro ce e na b le to c ur re nt

G oo d M an u fa ct ur in g P ra c-tic e

(c G

M P co m p lia nt p ilo t l ot p ro d u ct io n

C o n d u ct

G

LP

s af et y a n d t o xi ci ty s tu d ie m al m o d e l s ys te m s.

Id en tif y e n dp oi nt ic a l e ff ic ac y or it s su rr og a te . C o n d uc t st ud ie s to e va lu a te th e p h ar m a co ki ne tic s an d ph a r-m ac o dy na m ic s of c a n d id at e d ru g s.

S ta bi lit y st u di e s in iti at n se p e rio d o f no n-cl in ic a l a nd p re cl in ar ch s tu d ie s in vo lv in g p a ra m e tr ic d lle ct io n a n d a n al ys is in w e ll-d e fin ed s ys te m s w ith p ilo t lo ts o f ca n d id a te b io lo gi cs

/v a cc d uc ed a n d f u rt he r d ev el op m en t o f se le id at es

R es e ar ch r es ul ts s u pp o rt p ro p os in g a p o te n cy a ss ay pr o po si n g a m an uf ac tu ri ng pr es s a m e na b le to c

G M

P -c o m pl ia nt p ilo t l o t p ro du ct io n, id en tif yi n g a nd d e m on st ra tin g p ro of o f-co n ce pt f o r a su rr o ga te e ff ic ac y m a rk e r in m al m o d e l(s ap p lic a bl e to p re d ic tin g p ro te c-tiv e im m u ni ty in h um an s, a n d d em o ns tr at in g p re lim in a ry s a fe ty a n d e ffi ca cy a g ai n st a n a e ro so l c h al le n ge in a r e le va n t a n im a l m od el

C o n-d uc t

G

LP

s af et y an d to xi ci ty s tu d ie s in a n im a l m od el s ys te m s.

Id en tif y en dp oi nt s o f c lin ic a l e ffi ca cy o r its s u rr og at e in a n im al m o de ls b e ap pl ic ab le t o pr e d ic tin g pr ot e ct iv im u n ity in h u m an s.

C o nd uc t s tu di e s to e va lu a te im m un og en ic ity a s w e ll a s p ha rm ac o ki n et ic s an d ph a rm ac od yn a m ic s w he n ap pr o p ri b ili ty s tu di es in iti a th er d e ve lo pm en t of s el ec te d ca nd id at e vi ce s co m p ar e d to e xi st in g m od a lit ie s di ca tio ns f or u se a n d e q ui va le nc y de m o n st ra te d in m od e l s ys te m s.

E xa m pl e s in cl u d e d ev ic e s te st e d th ro u gh s im ul at io n in ti ss ue o r o rg an m od e ls o r a ni m a l m od el s if re qu ir ed

A ll co m p o n e nt s u pp lie rs /v e nd o rs a re id e nt ifi ed a n d q ua lif ie d;

v en do rs f or c rit ic al c om p on en ts ite d fo r cG M

P /Q ua lit y S ys te m R eg u la tio n (Q

S R co m p lia n ce

C om p on en t te st s, c o m p o n en t d ra w in gs d es ig n h is to ry f ile de si g n re vi e w an d an y D

M E a re v e rif ie d

P ro d uc t D e ve lo p m e n t P la n is d ra ft e d.

P re

-I nv es ti-g at io na l D e vi ce

E xe m p tio n

ID

E m e e tin d w ith

C e nt e r fo r D e vi ce s an d

R ad io lo g

H al th

C

D R

H fo r pr op o se d C la ss

II

I de vi th e

ID

E is p re pa re d an d s ub m itt ed t o

C D

R H

F or a

0( k) de te rm in e su bs ta nt ia lly e q u iv al e n t d ev ic e s a nd t he ir cl a ss ifi ca tio n, v al id a te f un c-tio ni n g m o de l, en su re in iti a l t es tin g is c o m p le te a nd v al id a te d a ta a n d re a di ne ss f or c G sp e ct io n

F irs t t e ch ni ca l t e st o f pr o to ty

/S

W s ys te m c om p o n e nt s a re in te g ra te d, a n d re a lis or tin g el e m en ts p lo ye d s o th at th e s ys b e t es te d in a s im u la te d e nv iro nm e nt

A ct u al in te rf a ce s to s u p po rt in g s ys te m s ec ifi e d a n d de ve lo p m en t be gi n s.

T R

L

D ec is io n C ri te ri o n

A d ec is io n p oi n ch ed a t w hi ch it is d e te rm in ed th at s u ff ic a on th e ca n di d a te d ru g e xi st in t he d ft n ic a l d at a pa ck ag e to ju st ify p ro ce e di n g w ith p re p ar at io n o f a n

I nv e st ig a tio n a l N ew D

(I

D a pp lic at n.

L

D ec is io n C ri te ri o n

A d ec is io n p oi n ch ed a t w hi ch it is d e te rm in ed th at s u ff ic a on th e ca n di d a te b io lo g ic /v a cc in e ex is d ra ft te ch ni ca l d at a p ac ka g e to ju st ify p ro ce ed in g w ith p re pa ra tio n of a n

IN

D a p pl ic at io n.

T R

L

D ec is io n C ri te ri o n

ID

E r e vi e w b y C

D R

H r es ul ts t o de te rm in e if th e in ve st ig at io n ca n b eg in

F or a

0( k) pr el im in ar y fin di n gs s u gg e st ic e w ill b e s u bs ta n tia lly e qu iv a le n t t di ca te d e vi ce

T R

L

D ec is io n C ri te ri o n

M e d ic al I n fo rm at ic s da ta le d ge r ep re se nt a tio n m o d-e ls a re im p le m e nt ed a s d at a an d/ or k n ow le d ge m a na g e m en t sy st e m s a n d te st ed in a la bo ra to ry e n vi ro n m e nt

E-11 le E

-1 . P ro p o s ed T

R L s f o r

M ed ic a l R D

T

E

C o n ti n u ed

T R

L

N A

S A

/D e si g n A cq u is it io n

G u id eb o o k T

R L

D e fi n it io n

C o m po ne nt a nd

/o r br e ad bo ar d v al id at io n in a r el e va nt e nv iro nm en t ( C on tin u ed

P h ar m ac e u ti g

s) N

1, N

P h ar m ac e u ti lo g ic s

, V ac c in es )N

1, N

M ed ic al D ev ic e sN

3, N

S u p p o rt in g

In fo rm at p p o rt in g In fo rm at p p o rt in g

In fo rm at vi e w e rs c on fir m a de qu ac y of in fo rm a tio n a on c a nd id a te d ru g in a d ra ft te ch ni ca l d ac ka g e to s up po rt p re p a ra tio n of

IN

D a p pl ic a-tio n.

D o cu m en ta tio n in t he d ra ft te ch ni ca l d ac ka g e co nt a in s d a ta fr om a n im a l p ha rm a co l-o gy a nd to xi co lo gy s tu di e s, p ro p os e d m a n u fa c-tu rin g in fo rm a tio n

, a n d cl in ic a l p ro to co ls fo r

P ha se c lin ic a l t es tin g.

R e vi e w er s co n fir m a de qu ac y of in fo rm a tio n a on c a nd id a te b io lo g ic /v a cc in e c on st ru ct ft te ch n ic al d a ta p a ck a ge t o su p p o rt p re p a-ra tio n of a n

IN

D a pp lic at io n.

D oc um e nt a tio d ra ft te ch n ic al d a ta p ac ka ge c o nt ai ns d fr om a ni m al p h ar m ac o lo gy a nd t o xi co lo g y st ud ie s, p ro p os ed m a nu fa ct ur in g in fo rm at io n a nd c lin ic a l p ro to co ls s ui ta bl e fo r

P h as e c lin i-ca l t e st in g

F or in ve st ig at io n of a C la ss

I

II

de vi ce to b eg um an s, t he f o llo w in g a re n ee de d

(1

A

’s a n d sp on so r’ s su m m ar y m in u te s o f p re

ID

E m ee tin g do cu m e nt a g re e m en ts a n d g e n er a l a de qu ac y o f in fo rm at io n a nd d a ta to s up po rt pa ra tio n a n d su bm is si o n of I

D E a pp lic a tio n a nd

2) a n

F D

A le tt er a ck no w le d g in g r e ce ip t o f

ID

E b y

C D

R H

T he in ve st ig a tio na l p la n cl in tr ia ls ca n b eg in a ft er da ys b ar ri ng a c lin ic a l ho ld f ro m t he F

D A or s o on e r if

C D

R H a pp ro ve s th e I

D E w ith in da ys

In t h e la tte r ca se

C D

R H w ill p ro vi d e w rit te n n ot ifi ca tio n.

bm itt ed

I D

E in cl u d e s in fo rm a tio n re ga rd in g th e s po n so r, in te n de d u se o f de vi ce ra tio n al e fo r u se o f de vi ce in ve st ig a tio na l p la n in st ru c-tio ns fo r u se o f de vi ce , l a be lin g, a nd in fo rm e d co ns en t.

F or a

(k de vi ce re vi e w e rs c on fir m p re lim i-na ry c la im th at t h e m e di ca l d e vi ce a pp e ar s su bs ta nt ia lly e q ui va le nt t o a p re d ic at e d e vi ce th e p ro p os e d cl a ss ifi ca tio n is c on si st en t

1C

F R

, t h e re is a fu nc tio ni n g m o de l, an in g r es u lts s u pp o rt s ub st an tia l e q ui va le n cy

E-12 le E

-1 . P ro p o s ed T

R L s f o r

M ed ic a l R D

T

E

C o n ti n u ed

T R

L

N A

S A

/D e fe n s e

A cq u is it io n G u id e b o o k T

R L

D ef in it io n

S ys te m /s ub sy st em m od e l o r pr ot ot yp e d e m on st ra tio n in a r el e va nt e nv iro nm en t

N A

S A

D ef en se A c q u is it id eb o o k T

R L

D es cr ip ti

A M

R M

C E q u iv al en t

T R

L D es cr ip ti o ar m ac e u ti g

s) N

1, N

P h ar m ac e u ti lo g ic s

, V ac c in es )N

1, N

M ed ic al D ev ic e sN

3, N

M ed ic al

IM

/I ic al

I n fo rm at p re se nt at iv e m od e l o r pr ot ot yp e sy st em

, w e ll b ey o nd t ha t o f

T R

L 5, is t e st e d va nt e n vi ro n m en t.

R e p re se nt s a m a jo r st in a t ec hn o lo gy ’s on st ra te d r ea d in e ss

E xa m pl es in cl ud e te st in g a p ro to ty pe in a h ig h fid el ity la bo ra to ry e nv i-ro n m e nt o r in a s im u-la te d op er at io ro nm t.

-I N

D m ee tin g (T yp e

B h el d w ith t he C e fo

D ru g E va lu a tio n a nd R es ea rc h

(C D

E R

I lic at io n is p re pa re d a nd s ub m itt e d.

P ha ic al t ria ls a re c on du ct ed t o d e m o ns tr at e sa fe ty o f ca nd id at e in a s m al l n um b e um an s un de r ca re fu lly c o nt ro lle d a nd in te ns el y m on ito re d cl in ic a l c o nd iti o n s.

E va lu a tio n o f p ha rm a co ki n et ic a nd p h ar m a co d yn am ic d a ta t o su pp or t th e d es ig n o f w e ll-co n tr o lle d sc ie nt ifi ca lly v a lid

P h as e st ud ie s.

P ro du ct io n t e ch n o l-o gi e s a re d e m on st ra te d th ro ug h pr od uc tio n sc al e c G

M P p la nt q u al ifi ca tio n

P re

-I N

D m ee tin g (T yp e

B h el d w ith t he C e

B io lo g ic s

E va lu a tio n a nd

R es ea rc h (C

B E

IN

a pp lic at io n is p re pa re d a nd s ub m itt ed

P h as e cl in ic al tr ia ls a re c o nd u ct e d to d e m o n st ra te s a fe ty o f c a nd id a te s in a s m a ll nu m b e bj e ct s un d e r ca re fu lly c o n tr ol le d a nd in te ns el y m o n ito re d cl in ic a l c o nd iti o n s.

E va lu a tio n o f im m u n o g en ic ity a nd

/o r p ha rm ac ok in et ic s an d ph ar m ac o dy n a m ic s d at a to s up po rt d es ig n o f

P h as e cl in ic al t ria ls

S u rr o g at e ef fic ac y m od e ls a re v a lid a te d

C lin ic a l t ria ls a re c on du ct e d to d e m on st ty o f ca nd id at e

C la ss I

II

m e di ca l d ev ic e sm ll n um b er o f hu m an s un d er c ar ef ul ly c on tr ol le d a n d in te n se ly m o ni to re d c lin ic a l c on d i-tio ns

C o m p on en t te st s, c om p on en t dr a w in gs d es ig n h is to ry f ile de si gn r e vi e w a nd a n y

D u pd a te d a n d ve rif ie d.

P ro du ct io n t ec h no lo g y de m on st ra te d t h ro ug h p ro du ct io n -s ca le c G n t q u a lif ic a tio n

F or

(k c om p on e n t te st s, c o m p o ne n t d ra w in gs de si gn h is to ry fi le d es ig n re vi e w

D M

R a re u p d at e d an d ve ri fie d . M a n u fa c-tu ri n g fa ci lit y is r e ad y fo r cG M

P in sp ec tio n.

A d va nc ed t ec h ni ca l t es tin g o f p ro to ty pe H

W /S

W s ys te m ud e in te rf ac es t o a ct o rt in g sy st em s, is c on d uc te d in a r e le va n t or s im u-la te d op e ra tio n al e n vi ro n m e

O t-pr o d u ct is fi n a l p ro to ty p e

T R

L

D ec is io n C ri te ri o n

D a ta f ro m

P ha ls m ee t cl in ic al s a fe ty r e qu ire m e nt s an d su pp or t p ro ce e d in g to P h as e cl in ic a l s tu d

L

D ec is io n C ri te ri o n

D a ta f ro m

P ha ic al t ria ls m ee t cl in ic al s a fe ty r eq ui re m ts s up po rt p ro ce ed in g to

P ha se c lin ic a l tr ia ls

T R

L

D ec is io n C ri te ri o n

D a ta f ro m t h e in iti a l cl in ic al in ve st ig at io n de m on st ra te t h at t

C ss

I

II

d ev ic e m ee ts s a fe ty r e qu ir e m en ts o rt p ro ce ed in g to c lin ic a l s af et y an d ef fe c-tiv en es s tr ia ls

F or a

0( k) in fo rm a tio n a nd d a ta d em on st bs ta nt ia l e q u iv al e n cy t o p re d ic at e d ev ic e or t p ro d uc tio n o f th e fin a l p ro to ty p e fin t e st in g in a m ili ta ry o p er a tio na l en vi ro n m e nt

T R

L

D ec is io n C ri te ri o n

M e d ic al I n fo rm at ic s da ta le d ge m a na ge m e nt s ys te m s a re t es te d w ith t ar ge t a pp lic at io ns in a la bo ra nv iro nm en t.

C o nf ig u ra tio n ag em en t ap pr oa el o pe p p o rt in g

In fo rm at p p o rt in g In fo rm at p p o rt in g

In fo rm at

P h a se

C lin ic a l T ri al s to b eg in th e fo llo w in g a re n e ed ed

: t he

F D

A ’s a n d sp o n so r’s m a ry m in u te s o f p re -I

N D m ee tin g do cu m gr ee m e nt s a nd g en e ra l a d eq ua cy o f in fo rm a-tio n a nd d a ta to s up po rt s u b m is si on o f lic at io n.

R e vi e w o f t he s ub m itt ed I

N D a p p li-ca tio n d o e s n ot r e su lt in a F

D A d ec is io n to p ut ic al h o ld o n P h as e c lin ic a l t ria ls w ith th e ca n di d at e dr ug e nt ry in to P ha se c lin ic a l t ria ls th e re lts

P ha se c lin ic al s tu d ie s h av e to d em o n-st ra te s a fe ty o f c a nd id a te d ru g.

A n u p d at ed

I lic at io n, a m en de d w ith a n e w c lin ic a l p ro to co l t o su pp or t

P ha se c lin ic a l t ria ls o r a su r-ro ga te t e st p la n a nd s u bm itt e d to t h e F

D A d oc u m e nt s th e a ch ie ve m en t of t hi s cr ite ri on

F or

P h a se

C lin ic a l T ri al s to b eg in th e fo llo w in g a re n e ed ed : t he F

D A

’s a n d sp o n so r’s m a ry m in u te s o f p re

-I N

D m ee tin g do cu m gr ee m e nt s a nd g en e ra l a d eq ua cy o f in fo rm a-tio n a nd d a ta to s up po rt s u b m is si on o f a n lic at io n.

R e vi e w o f t he s ub m itt ed

I N

D d oe s n ot r es ul t in a n F

D A d ec is io n to p ut a c lin ol d o n P h as e c lin ic a l t ria ls w ith th e ca nd id at e b io lo gi c/ va cc in e

F or e nt ry in to P ha se c lin ic a l t ria ls th e re lts

P ha se c lin ic al s tu d ie s h a ve t o de m o n-st ra te s a fe ty o f c an d id a te b io lo g ic

/v ac ci n e.

pd at e d

IN

D a m en d e d w ith a n e w c lin ic a l p ro to co l t o su p p or t

P h a se c lin ic al t ri a ls o r su rr og a te t es t pl a n a nd s u bm itt e d to th e F

D A do cu m e nt s ac h ie vi ng t hi s cr ite rio n.

D o cu m e nt a tio n fr om c lin ic al s tu dy r e su lts s h ow s th e c a nd id at e de vi ce is s af e

C ha ng es to th e in ve st ig a tio n al p la n th at r eq ui re

F D

A a p pr ov

(2

C

F R

2.

a re s ub m itt ed a s a su p p le m e n ta l I D

E a p pl ic at io n to th e F

D A

F or a

0( k) re vi e w e rs c o nf ir m a d eq ua cy o f d oc u m e nt e d co m p on en t t es ts co m p o w in gs de si gn h is to ry fi le d es ig n re vi e w ny

D M

R t o s u pp or t cl ai m o f su bs ta nt ia l e qu iv a le nc y a nd r e ad in es s fo r fin al te st in g in a m ili ra tio na l e n vi ro n m e nt

E-13 le E

-1 . P ro p o s ed T

R L s f o r

M ed ic a l R D

T

E

C o n ti n u ed

T R

L

N A

S A

/D e fe n s e

A cq u is it io n G u id e b o o k T

R L

D e fi n it io n

S ys te m p ro to ty pe d e m o ns tr at io n in a n o pe ra tio n al e nv iro nm e nt

N A

S A

D ef en se A c q u is it id eb o o k T

L cr ip ti o n

U S

A M

R M

C E q u iv al en t

T R

L D es cr ip ti o n s

P h ar m ac e u ti g

s) N

1, N

P h ar m ac e u ti lo g ic s

, V ac c in es )N

1, N

M ed ic al D ev ic e sN

3, N

M ed ic al

IM

/I ic al

I n fo rm a ti cs to ty pe n e ar o r at p la n n e d o pe ra tio e m

R ep re se nt s a m aj o r st ep u p f

L 6, r e qu iri n g de m o n-st ra tio n of a n a ct e m p ro to ty pe in a n op er at io na l e n vi ro nm

(e

.g in a n a ir cr af t, cl e, o r in s p ac e)

E xa m pl es in cl ud e te st in g th e p ro to ty pe in a te st be d ai rc ra ft

P h as e cl in ic al tr ia ls a re c o nd u ct e d to d e m o n st ra te in iti a l e ff ic a cy a n d ca pt ur e fu rt he r sa fe ty a n d to xi ci ty d a ta

P ro d uc t ac tiv ity e

.g p re lim in d e n ce o f e ff ic ac

y) is d et e rm in ed

P ro d uc t f e, d o se r a ng e , s ch ed ul e, a n d r ou te o f ad m in i-st ra tio n a re e st a b lis h ed fr om c lin ic al p ha rm ac ok i-n et ic a nd p ha rm a co d yn a m ic d at a.

P ha se c lin ls a re c o m pl et e d

D at a a re c ol le ct e d, p re se nt e d, a n d di sc u ss ed w ith C

D E

R a t pr e- P ha e tin g

T yp e B in s up po rt o f c on tin ue d dr ug el o pm en t.

C lin ic a l e n d p oi n ts a n d/ o r su rr o g at e e ffi ca cy m a rk er s an d t e st p la ns a g re e d to b y C

D E

R

P h as e sa fe ty a n d im m u n og en ic ity t ria ls a re c o n-du ct e d.

P ro d uc t i m m un og en ic ity a n d b io lo gi ca l a ct iv ity e.

g pr e lim in a ry e vi d en ce o f ef fic a cy ar e d et e rm in e d.

P ro du ct fi n a l d os e, d os e ra ng e, d ul e, a n d ro u te o f a dm in is tr at io n a re e st a b-lis h ed f ro m v ac ci ne im m u no ge ni ci ty a n d b io lo gi c a ct iv ity a n d w h en n e ce ss ar y, f ro m c lin ic a l p ha r-m a co ki n et ic s a n d p h ar m a co d yn a m ic s da ta

P h as e cl in ic al tr ia ls c o m pl e te d.

D at a ar e c ol le ct ed pr e se nt ed an d di sc u ss e d w ith C

B E

R a t p re -P h a se or s u rr o g at e ef fic ac

y) m e e

(T yp e

B in s up po rt o f c o nt in ue d d e ve lo p m en t o f th e b io lo g ic s/ va cc in es . C lin ic a l e n dp o in ts a nd /o r su rr o ga te e ff ic ac y m ar ke rs a nd te st p la n s ag y

C B

E R

C lin ic a l s a fe ty a nd e ff ec tiv e ne ss t ria ls a re c on d uc te d w ith a fu lly in te gr at e d

C la ss I

II

m e d ic e p ro to ty pe in a n o p er a tio na l e n vi ro nm e nt

C o nt in u at io n o f c lo se ly c on tr o lle d st ud ie s o f e ffe c-tiv en es s a n d de te rm in a tio n of s h o rt -t er m a d ve rs nt s a nd r is ks a ss o ci a te d w ith t h e c an di d du ct

F un ct io n al te st in g o f ca n d id at e de vi ce p le te d a nd c o nf irm ed

, r es u lti n g in f in al d o w n se le ct io n o f p ro to ty pe d e vi ce

C lin ic al s af et y ffe ct iv e ne ss t ria ls a re c om pl et ed

. F in a l p ro d uc t d es ig n is v a lid a te d a n d fin a l p ro to ty pe a n d/ o r in iti al c o m m e rc ia l s ca le d ev ic e is p ro du ce d.

D at a a re c ol le ct e d, p re se nt e d, a nd d is cu ss ed

R

H in s up po rt o f c on tin ue d d ev el o pm e a

0(

k) , f in a l p ro to ty p e a nd

/o r in iti al c om m er ci a l-s ca le d e vi ce a re p ro d u ce d an d te st ed ili ta ry o p er at io n al e n vi ro n m e nt

P ro to ty p e

H W

/S W s ys te m is n e ar o r at p la n ne d o pe ra tio na l s ys te m

A ct ua l s ys te m p ro to ty p e is d em on st ra te d in a n o pe ra tio na l e n vi ro n m e n d-us e rs fir st c ut r te

L

D ec is io n C ri te ri o n

P h as e cl in ic al s dy n o r su rr og a te t es t p la n ha s be en a pp ro ve d

T

R L

D ec is io n

C ri te ri o n

P h as e cl in ic al s dy n o r su rr o g a te t es t p la n ha s b e en a pp ro ve d.

T

R L

D ec is io n

C ri te ri o n

C lin ic a l e nd po in ts a p la n s a re a g re e d to b y

C D

R H

F or a

0( k) in fo rm a tio n a nd d a ta d em on st bs ta nt ia l e q u iv al e n cy t o p re d ic at e d ev ic e in a m ili ta ry o pe ra tio na l e nv iro nm e n t a or t p re p a ra tio n o f

0( k)

T R

L

D ec is io n C ri te ri o n

M ed ic a l I n fo rm a t-ic s d at a a n d kn o w le d g e m a n ag e m e n t s ys te m s a re o pe ra tio n al ly in te g ra te d an d te st e d rg et a p pl ic a tio n s in a n op er at io na l e nv iro nm e nt

S u p p o rt in g

In fo rm at p p o rt in g I n fo rm at p p o rt in g In fo rm a ti

A

’s s u m m ar y m in ut e s of p re -P ha se m ee s p on so r d is cu ss in g re su lts o f P h as e an d

P h as e tr ia ls a nd p ro to co ls o r te st p la ns p ro ec or d o f ag re e m e n ts a nd b a si s fo r sp o ns o ce e d w ith P h a se c lin ic al s tu d y or s ur ro g p la n.

A n u p da te d

IN

D a pp lic at io n, a m en de d w ith a n ew c lin ic al p ro to co l t o su p po rt

P h a ic al t ria ls o r su rr o g at e te st p la n a n d su b m itt e d to t h e F

D A

, d o cu m e nt s th e a ch ie ve m e nt o f cr ite ri on

F D

A ’s s u m m ar y m in ut e s of p re

-P ha se m ee s p on so r d is cu ss in g re su lts o f P h as e an d P h as e tr ia ls as w e ll as c lin ic a l p ro to co ls o r n s, p ro vi d e r ec or d o f a gr e em e nt s an d b a si s fo r sp on so r to p ro ce ed w ith P h as e c lin ic al s tu d rr og a te t es t p la n.

A n u p d at ed

IN

D a pp lic at n, e nd ed w ith a n ew c lin ic a l p ro to co l t o su p p or t P h as e cl in ic al tr ia ls o r su rr og a te te st p la n itt e d to th e

F D

A do cu m en ts a ch ie vi n g cr ite ri on

T he

F D

A ’s a n d sp on so r’s s u m m a ry m in u te s of t he ir m ee tin g do cu m e n ts a n y ag re em e nt s re a ch ed r eg a rd in g c on tin u ed d e ve lo p m h e C la ss

I

II

m ed ic a l d e vi ce

P M

A s he ll m od u le s (e

.g s ec tio n s of

P M

A ar e su b m itt ed t o C

D R

H b y sp on so r if is si o ns w e re p re vi o us ly a p pr ov e by

R H

F or a

0( k) do cu m e nt e d re su lts o f t es tin g in ra tio na l e nv iro nm en t s u pp or t sa fe ty ef fe ct iv e-n es s, a n d us e o f d ev ic e in a m ili ta ry o pe ra tio na l e nv iro n m en

E-14 le E

-1 . P ro p o s ed T

R L s f o r

M ed ic a l R D

T

E

C o n ti n u ed

T R

L

N A

S A

/D e fe n s e

A cq u is it io n G u id e b o o k T

R L

D e fi n it io n

A ct ua l s ys te m c om p le te d a nd q ua lif ie d th ro u gh t es t a n d d em o ns tr at io n

N A

S A

D ef en se A c q u is it id eb o o k T

R L

D es cr ip ti

A M

R M

C E q u iv al en t

T R

L D es cr ip ti o ar m ac e u ti g

s) N

1, N

P h ar m ac e u ti lo g ic s

, V ac c in es )N

1, N

M ed ic al D ev ic e sN

3, N

M ed ic al

IM

/I ic al

I n fo rm at ec h no lo gy h as b ee ve n to w o rk in it s fin a l fo rm a nd u n de r e xp e ct e d co nd iti o ns

In a lm os t a ll ca se s, t h is

T R

L re p re se nt s th e e nd o f t e m d e ve lo p m en t.

E xa m pl es in cl ud e d e ve l-o pm en ta l t es t an d e va lu a tio n o f th e sy st it s in te nd e d w e ap on e m to d e te rm in e if ee ts d es ig n sp ec ifi ca tio ns

Im pl e m en ta tio n of e xp an de d

P ha se c lin ic a l tr ia ls o r su rr og at e te st s to g at h e r in fo rm a tio n re la tiv e to t he s af et y an d e ffe ct iv en es s o f id at e d ru g

T ria ls a re c o nd u ct e d to e va lu a te t he o ve ra ll ri sk -b en ef it of a dm in is te ri n g id at e p ro d uc t an d to p ro vi d e an a d e qu at e b as is f o r dr u g la be lin g . P ro ce ss v a lid a tio p le te d a n d fo llo w e d b y lo t co n si st en cy re p ro du ci b ili ty s tu d ie s.

P re -N

D A

N e w

D ru g A pp lic at io

n) m ee tin g (T yp e

B h e ld w…