FDA_advisory_committee_outcomes.pdf

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McKinsey Center for Government

FDA AdvisoryCommittee Outcomes


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During the pre-market review process for drugsand medical devices, many regulatory agenciesseek unbiased advice from external experts toaddress areas of scientific or technical uncertainty.

The US Food and Drug Administration (FDA) inparticular has a well-defined process for obtainingexpert input from its advisory committees andincorporating the input into its review processes.FDA reviewers complete an initial review of aproduct application and identify questions whereexternal input is needed. The FDA then convenes

an advisory committee meeting and obtainsthe requested input through a combinationof presentations, discussion, and voting bycommittee members. After the meeting, FDAreviewers take into account the input receivedwhen making product approval decisions,although the recommendations of the committeeare not binding.

FDA advisory committee meetings are high-stakesinteractions, with many years of effort, millionsof dollars of investment, potential regulatoryapproval, and billions of dollars in potential salesfor a new drug riding on the outcome. However,despite the fact that sponsors recognize thecrucial nature of these meetings and are familiarwith the processes, we have found limitations inthe quantitative understanding of their outcomes.In this article, we have analyzed publicly availabledata on FDA advisory committee meetings with

the aim of helping to address these limitations. Weinvestigated several important issues, includingthe total number of meetings by type andtherapeutic area, the frequency with which newproduct applications are subjected to advisorycommittee meetings, consistency between theadvisory committee votes and FDA approvaldecisions, and the duration between an advisorycommittee meeting and the final FDA approvaldate for a product.

FDA AdvisoryCommittee Outcomes

Philip Ma, Navjot Singh, Jeff Smith, Seth Townsend

FDA advisory committee meetings are high-stakes interactions, with many years of effort,millions of dollars of investment, potential regulatory approval, and billions of dollars inpotential sales for a new drug riding on the outcome. We have analyzed publicly availabledata and established a fact base that provides all stakeholders with a better characterizationand greater transparency into the outcomes of advisory committee meetings. We alsoconsider the implications for how sponsors can use this information to improve R&Ddecision-making.


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Analysis

We conducted an outside-in analysis of theoutcomes of FDA advisory committee meetingsheld for drugs during the decade from 2001to 2010 by reviewing publicly accessiblematerials, including meeting minutes, postedon the FDA’s website.

Of the 543 total advisory committee meetingsheld for drugs in the 2001-2010 period (Exhibit

1a), 281 were focused on a single product, ofwhich 190 were for original new drug applications(NDAs) and biologics license applications (BLAs),and 91 were for supplemental NDAs or BLAs.

The distribution of meetings by therapeutic areais shown in Exhibit 1b. With regard to novel drugs,37% of FDA-approved new chemical entities ornew biological entities in the 2001–2010 periodwere the subject of an advisory committee meeting(Exhibit 1c). This percentage increased from

32.8% in the 2001–2005 period to 41.4% in the2006–2010 period, suggesting a slight increasein the FDA’s use of advisory committee input tohelp inform product approval decisions. Additionaldata analysis shows that new biologics, prioritystatus applications, and orphan drugs were thesubject of more meetings, on a percentage basis,than new chemical entities, standard applications,and non-orphan drugs.

We considered in detail a subset of 63 of the 190meetings related to original NDAs or BLAs, atwhich committee members were asked to votefor or against approval of the drug of interest. Inthe analysis, we looked at the voting record todetermine whether the committee provided anendorsement for the approval of the drug (identi-fied as a simple majorit y of votes recommendingapproval). We then identified whether the FDA

Voting on approvalquestion (63)

Voting, all others (70)

No voting (57)

Voting, all others (26)

No voting (43)

Voting on approvalquestion (22)

Original NDAsor BLAs (190)

SupplementalNDAs or BLAs (91)

AC meetingsfor drugs2001–2010 (543) NDA- or BLA-

focusedmeetings (281)

All othermeetings (262)

Exhibit 1 | Characteristics of FDA advisory committee meetings between 2001 and 2010.

a | Overall characteristics of 543 US Food and Drug Administration (FDA) advisory committee (AC) meetings held for drugs between 2001 and 2010.b | Distribution by committee of the 281 meetings focused on new drug applications (NDAs) or biologics license applications (BLAs).c | Percentage of approved new molecular entities (NMEs) that were the subject of an AC meeting. NBE, new biological entity; NCE, new chemical entity.

Date Molecule type

Priority status Orphan status

A l l N M

E s ( 2 0 0

1 – 2 0

0 5 )

A l l N M

E s ( 2 0 0

6 – 2 0

1 0 )

N C E s

N B E s

S t a n d

a r d

P r i o r i t y

N o n - o

r p h a n

All NMEs (2001–2010)

ca

b

32.8

41.443.8

31.6

43.8 42.9

37.0035.235.9

21.4%

13.5%

8.2%8.2%

7.5%

6.4%

5.3%

29.5%

P e r c e n t a g e

50

40

30

20

10

0

O r p h

a n Oncological drugs AC Cardiovascular and renal drugs AC Anti-infective drugs AC Endocrinological and metabolic drugs AC Antivi ral drugs AC Psychopharmacological drugs AC Arthr itis AC All others

281meetings


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approved the drug, and for those drugs that wereapproved we also identified the duration of timebetween the meeting and the approval date.

As shown in Exhib it 2a, the FDA’s approvaldecisions have been broadly consistent with therecommendations of its advisory committees.

The FDA approved 88% of the original NDAsor BLAs that were endorsed by its advisorycommittees, and did not approve 86% ofthose that the committees did not endorse. In

addition, in those instances when the approvaldecision made by the FDA differed from therecommendation of the advisory committee,the FDA did so at the same rate regardlessof whether the panel endorsed approval. Thesensitivity and specificity of advisory committeerecommendations as a test for FDA approval is96% and 67%, respectively. In addition, at 78%of advisory committee meetings the membersrecommended drug approval.

Exhibit 2b shows that in 87% of committeemeetings the result was either a clear “yes”or “no” vote. One possible explanation for thisobservation is that the committee membershave a deep expertise in their field and canreadily address the areas of uncertainty in theapplication. An alternative explanation could be a“herding effect” in advisory committee meetings,where one or more influential members convinceother panel members of the ir point of view. Theopen, role-call voting system of most meetings

could fur ther contribute to this effect. In practice,it seems likely that both explanations contributeto this observation.

The association between the strength of theendorsement by the committee (as measuredby the percentage of panel members voting forapproval) and the duration between the advisorycommittee meeting and FDA approval date isshown in Exhib it 2c. As might be anticipated,

a | Summary of US Food and Drug Administration (FDA) advisory committee recommendations and approval decisions.b | Clarity of outcome of voting decisions. We considered the effect of the strength of the advisory committee endorsement by creating three equalcategories: ≤33% endorsement for approval; between 33% and 67% endorsement for approval; and ≥67% endorsement for approval. In 87% ofcommittee meetings, the result was either a clear “yes” or “no” vote.c | Association between the strength of the endorsement by the advisory committee, as measured by the percentage of panel members voting forapproval, and the median duration between the meeting and the FDA approval date. The duration varies inversely with the strength of the endorsement.

Exhibit 2 | Analysis of a subset of 63 FDA advisory committee meet ings that included votes for or against theapproval of a new drug between 2001 and 2010.

43 6

2 12

a Sensitivity: 95.6% Specicity: 66.7%

Did the FDA approve the product?

Yes

Y e s

D i d

t h e a d v i s o r y c o m m

i t t e e

r e c o m m e n

d a p p r o v a

l ?

N e g a t

i v e

p r e d

i c t i v e

v a l u e : 8 5

. 7 %

P o s i

t i v e

p r e

d i c t i v e

v a l u e :

8 7 . 8

%

No

N o P

e r c e n t a g e o f m e e

t i n g s

Percentage of advisory committeevote in favour of approval

b 80

70

60

50

40

30

20

10

0

19.112.7

68.2

≤33 33–67 ≥67

c

N u m

b e r o f

d a y s

Percentage of advisory committeevote in favour of approval

800

700

600

500

400

300

200

100

0

699

191

≤33 33–67 ≥67

140


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the duration varies inversely with the strengthof the endorsement, suggesting that stronglyendorsed products tend to be approved on thefirst review cycle, whereas products that are notas strongly endorsed could be associated withmultiple review cycles. Our results also showthat advisory committees endorse approximatelythe same percentage of products for approvalas the FDA approves applications (~75%). Thissuggests that the FDA is not disproportionatelypre-screening either clear approvals or rejectionsprior to selecting applications to review at anadvisory committee meeting. Instead, theresults are suggestive of a two-cohort model ofapplications based on whether FDA reviewersfeel they have sufficient input and knowledge tomake approval decisions without an advisorycommittee meeting. This supports the notionthat advisory committees have a crucial rolein providing necessary input to FDA reviewersduring the pre-market review process.

ImplicationsWe believe that these results have importantimplications for companies that are preparing forpotential advisory committee meetings. Giventhe characteristics of advisory committeesthat we have described here, we believe thatthe use of bodies akin to advisory committeescould be considerably expanded by industry,and could be a major driver for improveddecision-making. Companies currently usemock advisory panels to help rehearse andprepare for advisory committee meetings.However, given the sensitivity and specif icity ofthe approach, companies may be better served

by incorporating the approach into decision-making, not merely preparation. This could beapplied at different points in the life cycle of aproduct where impor tant investment decisionsare made—for example, following Phase IIdevelopment—in addition to pre-submission.

Editor’s note: This article was previously publishedin Nature Reviews Drug Discovery .


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