Journal club presentation evaluating a systematic review of supplemental indication approval practices.

1. JOURNAL CLUB
Sandeepkumar Balabbigari
Ernest Mario School of Pharmacy, Rutgers University
Cycle 5 2016, Capital Health Regional Medical Center
1
CHARACTERISTICS OF EFFICACY EVIDENCE SUPPORTING APPROVAL OF SUPPLEMENTAL INDICATIONS
FOR PRESCRIPTION DRUGS IN UNITED STATES, 2005-14: SYSTEMATIC REVIEW
Background The process of obtaining drug approval from the FDA is a vast and encompassing process. It requires an
enormous amount of data regarding the safety and efficacy of the drug in both animal and human models. This
data can be obtained through pre-clinical and clinical trials, the latter of which provide an insight into the
pharmacokinetic and pharmacodynamic properties of the drug in the human body. Clinical trials to show safety
and efficacy can be designed in numerous fashions and can vary between drugs given the therapeutic area for
their intended approval. Drugs may be tested against an active comparator, a placebo, or no comparator at all.
The results of the drug therapy can then be measured as either a qualitative clinical outcome, a quantitative
rating on a clinical scale, or a surrogate outcome which may correlate with a clinical endpoint. After initial
indication approval, drug manufacturers may apply for supplemental indications.
Supplemental indications may receive FDA approval by providing data through the use of the aforementioned
clinical efficacy trials. However, often times, the efficacy trials for supplemental indications are less rigorous
and may potentially increase the availability of drugs in conditions that have been poorly investigated. Despite
the lower quality evidence that may be produced from efficacy trials for supplemental indications, it has been
found that, since 1987, the FDA has been approving more indications and doing so with a shorter review time.
Recently, the 21st
Century Cures Act has been introduced as new legislation to spur technological advancements
in medicine. While it proposes an increased spending on research and greater transparency of clinical trial data,
the legislation also calls for accelerated approval for new drugs and drug uses. For instance, the bill supports the
use of surrogate outcomes as opposed to clinical endpoints to reduce costs of clinical trials and shorten the time
to receive FDA approval. Some surrogate markers have shown clinical utility, while other markers have,
unfortunately, not resulted in patient benefit and may have possibly resulted in patient harm.
The data needed for the approval of supplemental indications has become less rigorous over the years.
Ultimately, a clinician’s outlook on the changes in the drug approval process will hinge on patient outcomes.
Further studies must be conducted to determine whether patients are benefitting or being harmed from the
increased and expedited approval of drugs based on lower quality evidence.
Previous
Trials
Downing NS, Aminawung JA, Shah ND, et al. Clinical trial evidence supporting FDA approval of novel
therapeutic agents, 2005-2012. JAMA 2014;311:368-77.
- Characterized pivotal efficacy trials for novel agents that received initial indication approval between 2005
and 2012.
- Cross sectional analysis of pivotal efficacy trials for initial approval of novel therapeutic agents
- Efficacy trials were classified by study design features: randomization, blinding, comparator, and endpoints.
- The results revealed that from 2005 to 2012, 188 novel drugs were approved for 206 indications based on
the data of 448 pivotal efficacy trials. 89.3% of trials were randomized, 79.5% were double-blinded, and
87.1% were either active- or placebo-controlled. 33.3% of the pivotal trials used clinical outcomes as their
endpoint, 17.9% used clinical scales, and 4.53% used surrogate outcomes. The median number of patients
in all trials was 760, ranging from 260 to 1550.
- The investigators concluded that the design of the pivotal trials that resulted in initial indication approval
varied by the therapeutic area. Thus, when making clinical decisions based on the strength of clinical trial
evidence, it is important to consider the trial design.
DiMasi JA. Innovating by developing new uses of already-approved drugs: trends in the marketing
approval of supplemental indications. Clin Ther 2013;35:808-18.
- Analyzed the trends in supplemental indication approvals for FDA-approved drugs and biologic agents.
- Data set comprised of supplement indication approvals between 1998 and 2011. The types of supplemental
indications, time from submission of an application to FDA approval, and the therapeutic-significance
ratings for approved applications were examined.
- The results demonstrated a stable number of new supplemental indication approvals over-time; 51.1% of
supplemental indication approvals between 1998 and 2011 occurred during 1998-2004 and 48.5% during
2005-2011. The mean time between supplemental indication application submissions to approval was 13.1
months during 1998-2004 and 11.3 months during 2005-2011; however, this time length varied given the
therapeutic category, patient population, and therapeutic-significance rating of the drug.
- The investigators concluded that the approval of supplemental indications has remained stable throughout
the years largely in part due to the incentives provided by the FDA for studies regarding pediatric
indications. Approval times for supplemental indications have also declined due to legislative changes.

2. JOURNAL CLUB
Sandeepkumar Balabbigari
Ernest Mario School of Pharmacy, Rutgers University
Cycle 5 2016, Capital Health Regional Medical Center
2
Why this
Study?
The approval of initial and supplemental indications are both held to the same standard of providing clinical
efficacy data regarding their use for a specific therapeutic purpose. Prior to this systematic review, only the
average regulatory review times for supplemental indications have been studied. This review aims to assess the
differences in efficacy trials between those that supported initial indications and those that supported
supplemental indications.
GENERAL STUDY OVERVIEW
Title/Citation Characteristics of efficacy evidence supporting approval of supplemental indications for prescription
drugs in United States, 2005-14: systematic review
Wang B, Kesselheim AS. Characteristics of efficacy evidence supporting approval of supplemental indications
for prescription drugs in United States, 2005-14: systematic review. BMJ : British Medical Journal.
2015;351:h4679. doi:10.1136/bmj.h4679.
Funding Funding was provided by Greenwall faculty scholars program in bioethics and the Harvard program in
therapeutic science. There was no funding for this study from the industry. No competing interests were
declared.
Trial design Systematic review of supplemental indication approval applications between 2005 and 2014 found in the
Drugs@FDA database.
Objectives To compare the types of comparators and endpoints used in clinical trials for drugs’ initial indication approvals
to those of the supplemental indication approvals.
METHODS
Inclusion
criteria
- Supplemental indication approvals for drugs that were considered novel agents at the time of their initial
indication approval
Exclusion
criteria
- Supplemental indication approvals for drugs that were not considered to be novel agents at the time of their
initial indication approval
- Supplemental approvals related to labeling or label revisions and changes or additions in manufacturing
- Supplemental indication approvals for contrast and diagnostic agents
Outcome
measures
The types of comparators and endpoints that were used in the efficacy trials for drugs’ initial and supplemental
indication approvals. The types of comparators that were assessed include: active comparator, placebo, or none.
The types of endpoints that were assessed include: clinical outcomes, clinical scales, and surrogate outcomes.
Statistical
analyses
Pre-specified χ2
tests were conducted to assess the study comparators and endpoints used in efficacy trials to
achieve supplemental indication approval.
Pre-specified χ2
tests were conducted to compare the efficacy trials for a given drug’s initial indication approval
and supplemental indication approval.
RESULTS
Enrollment Between 2005 and 2014, the FDA approved 16,855 supplement applications of which 438 were for
supplemental indication approvals and 16,417 were for regulatory actions other than the approval of
supplemental indications.
Of the 438 supplemental indication approvals, 143 met exclusion criteria because they pertained to drugs that
were not novel agents at the time of initial approval or were for contrast and diagnostic agents.
In total, 164 unique drugs, which were all novel agents at the time of their initial approval, received at least one
of these supplemental indication approvals. Overall, 295 supplemental indication approvals met inclusion
criteria.

3. JOURNAL CLUB
Sandeepkumar Balabbigari
Ernest Mario School of Pharmacy, Rutgers University
Cycle 5 2016, Capital Health Regional Medical Center
3
New Indication Modified Indication Expanded Population
137 (46%) 93 (32%) 65 (22%)
Investigators classified each of the supplemental indication approvals into exclusive categories.
Of the 65 supplemental indication approvals for expanded populations, 61 were for the pediatric population
Oncology Infectious
Disease
Cardiovascular Disease
(including DM, HTN, HLD)
Psychiatry Musculoskeletal &
Rheumatology
80 (27%) 44 (15%) 35 (12%) 34 (12%) 30 (10%)
The therapeutic areas that received the most number of supplemental indication approvals are listed.
Results
There were significant differences in the type of comparators used in the efficacy trials for the supplemental
indication approvals.
The majority of modified indications were supported by efficacy trials that used at least one active comparator
whereas only 30% of new indications and 11% of expanded population indications were approved based on
active-controlled study designs.
Additionally, 34% of expanded population indications were approved based on uncontrolled efficacy trials. In
fact, 9 (14%) of the expanded population indications were approved without any efficacy trials.
There were no significant differences in the type of endpoints used in the efficacy trials for the supplemental
indication approvals.
The 164 unique, novel agents that met inclusion criteria for this systematic review, were initially approved for a
total of 201 indications. Between 2005 and 2014, a total of 137 new supplemental indications were approved
for these drugs. There was a statistically significant difference in the number of supplemental new indications
and initial indications that were approved based on active-controlled and placebo-controlled trials.
The use of clinical scales is the only statistically significant difference in the trial endpoints between the trials
supporting initial indications and those supporting supplemental new indications.
New Indication
(n=137)
Modified Indication
(n=93)
Expanded Population
(n=65)
P Value
Active
Comparator
41 (30%) 47 (51%) 7 (11%) <0.001
Placebo
Comparator
77 (57%) 39 (42%) 26 (40%) 0.03
No
Comparator
18 (13%) 5 (5%) 22 (34%) <0.0001
New Indication
(n=137)
Modified Indication
(n=93)
Expanded Population
(n=65)
P Value
Clinical
Outcomes
44 (32%) 28 (30%) 14 (22%) 0.29
Clinical
Scale
43 (31%) 23 (25%) 17 (26%) 0.50
Surrogate
Outcomes
50 (36%) 41 (44%) 25 (38%) 0.51
Active
Comparator
Placebo
Comparator
No
Comparator
New Indication (n=137) 41 (30%) 77 (57%) 18 (13%)
Initial Indication (n=201) 90 (45%) 85 (42%) 25 (12%)
P Value 0.007 0.01 0.83
Clinical
Outcome
Clinical
Scale
Surrogate
Outcome
New Indication (n=137) 44 (32%) 43 (31%) 50 (36%)
Initial Indication (n=201) 78 (39%) 37 (18%) 87 (43%)
P Value 0.22 0.005 0.23

4. JOURNAL CLUB
Sandeepkumar Balabbigari
Ernest Mario School of Pharmacy, Rutgers University
Cycle 5 2016, Capital Health Regional Medical Center
4
‘AUTHORS’ CONCLUSIONS
The authors of this systematic review concluded that there were variations in the level of evidence that was used to support
supplemental indication approval. In general, it was found that the efficacy trials used to support supplemental indications were
less likely to utilize active comparators or clinical outcome endpoints in the trial design. Further exploration revealed that
expanded population supplemental indications had the lowest amount of clinical outcomes data and were supported by the fewest
number of active-comparator trials.
This was a point of concern for the authors as the vast majority of expanded population supplemental indications were for the
pediatric population. In fact, approximately half of these supplemental indications for pediatric patients were approved based on
uncontrolled studied or studies that only extrapolated data from previous adult studies. The authors offered some possible
considerations to help improve the quality of data used for supplemental indication approval. For example, the Best
Pharmaceutical for Children Act can be modified to incentivize drug manufacturers to provide higher quality data when seeking
an expanded population supplemental indication in pediatric patients.
Additionally, changes to the 21st
Century Cures legislation may permit the FDA to require higher quality evidence and to more
closely examine efficacy data for supplemental indications. The authors also call for better enforcement of the required post-
approval confirmatory studies to better identify any safety issues in a drug’s new use.
Examining the efficacy data with which supplemental indications are approved will promote improved knowledge of a drug’s
benefits and risks in treating a certain condition. Overall, patients and clinicians will have the necessary resources available to
choose the safest and most effective therapy.
GENERALIZABILITY/CRITIQUE/DISCUSSION
Criteria - The inclusion criteria was appropriate given the objective of the study. By only including supplemental
indications for agents that were considered to be novel agents in their class, it allowed the investigators to
truly reveal the differences in efficacy trials for initial indications and supplemental indications. It is
feasible that non-novel agents may be approved with less scrutiny and lower quality evidence and thus do
not adequately reflect the differences in efficacy trials between initial and supplemental indications.
- The exclusion criteria was also appropriate as it removed factors that do not hold as much clinical relevance
as novel therapeutic agents. By excluding both of these factors, this systematic review is more clinically
applicable.
- At the same time, however, the exclusion of supplemental indications for non-novel agents is not
representative of current real world scenarios.
Outcomes - The assessment of the differences in comparators and endpoints between efficacy trials supporting initial
indications and efficacy trials supporting supplemental indications was appropriate given the objective of
the study. However, much of the data was derived from FDA approved drug labels rather than the detailed
FDA medical reviews that spell out the details of all clinical trials associated with the indication’s approval.
- The investigators only evaluated comparators and endpoints for the efficacy trials. Other trial design
aspects, such as patient randomization, patient population baseline characteristics, trial duration, may have
provided a deeper insight into the use of one type of comparator and endpoint over another.
- When assessing if an efficacy trial for a supplemental indication utilized an active compactor as opposed to
a placebo or no comparator at all, the investigators should have determined if a reasonable alternative or
established standard of care already existed for the indication. Additionally, the investigators should have
also considered the ethics of placebo controls for the given indication.
- Additionally, the investigators should have also considered appropriateness of using clinical outcomes,
clinical scales, or surrogate outcomes in efficacy trials for a given indication.
Statistics - The χ2
test was an appropriate statistical measure as this study assessed nominal data involving unrelated
groups. This test will help to determine the likelihood that the use of a certain comparator and endpoint in
an efficacy trial is independent of the fact that the efficacy trial is for an initial or supplemental indication.
- Power was not reported for this study. Some comparisons yielded statistically significant differences so
power for this study may not be necessary. However some comparisons, did not show statistical
significance. Thus the use of power in determining a sample size may have been appropriate as it allows the
investigators to gather more robust data to definitively determine if it is or is not statistical significant.
RECOMMENDATION
Given the clear difference in the level of evidence supporting initial indication approval vs. supplemental indication approval, I
believe it is prudent for healthcare providers to more closely examine the efficacy data that forms the basis for a drug’s
supplemental indications. Additionally, legislative changes have helped to promote the acceptance of lower quality evidence for
supplemental indication approval and thus must be re-visited. As it stands, I believe the therapeutic benefits of increased approved
uses for drugs do not outweigh the safety risks of basing those uses on lower quality data. A drug’s supplemental indications
should be held to the same efficacy standard as its preceding initial indications.

5. JOURNAL CLUB
Sandeepkumar Balabbigari
Ernest Mario School of Pharmacy, Rutgers University
Cycle 5 2016, Capital Health Regional Medical Center
5
References:
1. Wang B, Kesselheim AS. Characteristics of efficacy evidence supporting approval of supplemental indications for
prescription drugs in United States, 2005-14: systematic review. BMJ : British Medical Journal. 2015;351:h4679.
2. Downing NS, Aminawung JA, Shah ND, et al. Clinical trial evidence supporting FDA approval of novel therapeutic agents,
2005-2012. JAMA 2014;311:368-77.
3. DiMasi JA. Innovating by developing new uses of already-approved drugs: trends in the marketing approval of supplemental
indications. Clin Ther 2013;35:808-18.
4. Goldberg NH, Schneeweiss S, Kowal MK, et al. Availability of comparative efficy data at the time of drug approval in the
United States. JAMA 2011;305:1786-9.
5. Munos B. 2014 New drug approvals hit 18-year high. 2015. www.forbes.com/sites/bernardmunos/2015/01/02/the-fda-
approvals-of-2014/.
6. Kesselheim AS, Wang B, et al. Trends in utilization of FDA expedited drug development and approval programs, 1987-2014:
cohort study 2015;351:h4633
7. Avorn, J. & Kesselheim, A.S. The 21stCentury Cures Act — will it take us back in time? N. Engl. J. Med. 372, 2473–
2475(2015).
8. Sullivan MG. More expanded drug indications approved on less rigorous evidence. 2015.
http://www.pm360online.com/more-expanded-drug-indications-approved-on-less-rigorous-evidence/