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.

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.

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

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.

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/