VOI News

GDUFA leads to major efficiency gains in the FDA’s Office of Generic Drugs

For the first time since the FDA’s Office of Generic Drugs (OGD) was authorized to address its approval backlog with industry-paid user fees, the agency has provided a top-level view of activity in the form of its first annual report. The highlight for the generic industry is the 580 approvals (along with 146 tentative) that were issued in 2015, which includes a record-setting 99 combined approvals in December alone.

The agency, which is in negotiations with Congress to reauthorize the user fee project, can also point to dramatic operational improvements. With roughly $300 million per year provided through user fees, the agency has been able to clear almost 90% of the backlog in generic applications. The backlog, which is defined as applications that were received before October 1, 2012, initially included 2,866 ANDAs and around two-thirds as many applications for substantial changes on previously approved drugs. At the end of the reporting period, 84% of the former and 88% of the latter had been resolved in one way or another.

As is frequently the case, however, it pays to read the fine print: specifically, the most common form of ANDA-resolution by a substantial margin was “Complete Response with an Inspection.” According to the agency, this constitutes “a written FDA communication to an applicant usually describing all of the deficiencies that the agency has identified in an application that must be satisfactorily addressed before it can be approved.” If a high percentage of the sponsors of these applications take steps necessary to address the deficiencies identified in their complete response letters, a lot of the “resolved” applications could wind up back in the agency’s workload. Given the speed with which the generic industry changes, it is possible that many sponsors walked away from these applications years ago but the complete response approach does not have the same level of finality as one might expect.

Less ambiguous and of perhaps greater importance for the future is the fact that the ANDA filing backlog has been eliminated for all practical purposes. Filing can be thought of as a “pre-review review.” In other words, this is the period during which the FDA performs an initial audit of a submitted application in order to determine whether it can move forward to the substantive review phase. As recently as August 2014, more than 1,100 applications were stuck in this particularly frustrating form of limbo. In a very short period of time, the OGD addressed this backlog and is now making filing decisions in an average of 40 days, with only one percent taking longer than two months.

Study looks at vial size and cost of left over cancer drugs

To estimate costs associated with infused drugs discarded because they are left over after administration to a patient, Peter Bach of the Center for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Center and colleagues looked at 20 infused cancer agents with single-vial packaging and weight-based dosing. In the January 20, 2016 issue of BMJ, they report a range of 1% to 33% in the amount of drug left over following administration. After accounting for differences in drug price, they found that the value of products that would not be received by a patient under recommended dosing scenarios equals $1.8 billion or 10% of the combined 2016 sales for these drugs. Roughly $1 billion more is paid to hospitals, clinics, and other providers in the form of “buy and bill” markups for left over portions.

In most other settings, it would be a simple matter to set aside the left over product and use if for the next “customer” but, as is usually the case, the rules and practices governing pharmaceuticals are not so straightforward. The CDC states that single-use vials “should only be used for a single patient” because “these medications typically lack antimicrobial preservatives and can become contaminated.” Although the FDA’s position is not as clear cut as the CDC’s, it also cites microbial contamination along with medication errors as factors that “may” cause problems. CMS’ position, however, is that “it is permissible for healthcare personnel to administer repackaged doses derived from [single-dose vials] to multiple patients, provided that each repackaged dose is used for a single patient in accordance with applicable storage and handling requirements.” Meanwhile, the US Pharmacopeial Convention allows sharing only if the remaining drug is used within six hours and handled by specialized pharmacies.

Exploring Design Elements of Cancer Pivotal Trials

This is the third in a series of blog posts VOI Consulting will publish based on high-level examination of the company’s new insiteinvestigator™ database. It addresses pivotal trial design for cancer drugs gaining approval during the 2005 to 2011 period.

Pivotal Trial Design

The insiteinvestigator™ database also captures elements of pivotal trial design. Using comparisons between solid tumors and hematological malignancies, the following discussion looks at several of the more important design features: primary endpoints, number of arms, and control types.

Primary Endpoints

Overall survival, defined as the time from randomization until death from any cause, is the FDA’s gold standard for drug approval in the cancer field. From a development standpoint, however, it is the most difficult and costly endpoint to demonstrate as it requires higher patient populations and longer follow-up periods.  As we have seen in the preceding section, the FDA is often willing to accept less than gold standard evidence when doing so will make new therapies available if the data is sufficient to show that these new therapies are both safe and effective.

Indeed, as shown in Figure 1, overall survival served as the primary endpoint in only 18% of all pivotal trials during our time period. Although it was the most common primary endpoint in solid tumors, it still represented just one-third of such trials, barely edging out progression free survival which was the primary endpoint in 29% of solid tumor pivotal trials. More striking is its near-total absence in hematologic malignancies where only 4% of pivotal trials featured overall survival as a primary endpoint. In these cancers, response rate and the closely related duration of response/clinical benefit are the predominant primary endpoints, having been used to support 59% of all approvals.

Figure 1 - Primary Endpoints in Cancer Pivotal Trials 2005-2011

 Insiteinvestigator is VOI’s proprietary database containing detailed information on design, endpoints, populations, size, placement, timelines, efficacy outcomes, and safety results for every pivotal trial supporting a cancer drug approved by the U.S. FDA from 2005 through 2011.

Cancer Drug Approval Requirements

This is the second in a series of blog posts VOI Consulting will publish based on high-level examination of the company’s new insiteinvestigator™ database. It addresses FDA approval requirements for cancer drugs approved between 2005 and 2011. 

Approval Requirements

As a rule, the FDA recommends that applications include data from “at least two adequate and well-controlled clinical trials” as a condition of standard drug approval.[1] In cancer, however, the high degree of unmet medical need and the urgency of offering new treatments for potentially fatal diseases mean that approvals are based on a wide range of clinical data packages.This is demonstrated in Figure 1 which shows that the “two adequate and well-controlled trials” standard is actually an unusual occurrence in cancer as only 2% of all indications received approval using this approach. Indeed, approved applications have been based on pivotal trials ranging from as little as a single Phase I pharmacokinetic study (asparaginase Erwinia chrysanthemi, approved in 2011 as part of a combination regimen for acute lymphoblastic leukemia) to as much as three separate Phase 3 trials (rituximab’s 2006 approval for use with CHOP chemotherapy in newly diagnosed Non-Hodgkin Lymphoma patients).Despite the variance, certain thresholds are evident. For example, 75% of all applications and 56% of orphan indications were directly supported with at least one Phase 3 trial. Standards are predictably higher for non-orphan indications, where 88% of applications included a Phase 3 trial. Of indications approved without Phase 3 support, most were for patients who had failed or who demonstrated intolerance to earlier lines of therapy which is understandable given the limited treatment options available to these groups.In addition to demonstrating the range of required data, Figure 1 also reveals that 59% of all indications were approved with a single Phase 3 trial. Nearly three-quarters of all non-orphan drugs fall in this category and it is the most common scenario for orphan drugs as well. In the absence of specific guidance from regulatory agencies, this may serve as the best available proxy for establishing the scope of a clinical trial program necessary to gain approval.

Figure 1 - Number and Type of Pivotal Trials for Approved Cancer Drugs 2005-2011


insiteinvestigator™ is VOI’s proprietary database containing detailed information on design, endpoints, populations, size, placement, timelines, efficacy outcomes, and safety results for every pivotal trial supporting a cancer drug approved by the U.S. FDA from 2005 through 2011.

[1] Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. Food and Drug Administration. May 2007

Cancer Drug Approval Trends 2005 - 2011


This is the first in a series of blog posts VOI Consulting will publish based on high-level examination of the company’s new insiteinvestigator database which contains information on design, endpoints, populations, size, placement, timelines, efficacy outcomes, and safety results for every pivotal trial supporting a cancer drug approved by the U.S. FDA from 2005 through 2011. Each article will examine a specific topic to include: cancer drug approval trends, approval requirements, pivotal trial design, size, location, and key timing elements such recruitment periods and patient accrual per site within specific cancer types.

Cancer Drug Approval Trends

From the start of 2005 through the end of 2011, 48 different drugs were approved by the FDA for 83 different indications, of which 38 were new and 45 were supplemental. One hundred pivotal trials supported these approvals, an average of 1.2 trials per indication. (Note that there is some latitude in what constitutes a pivotal trial. For our purposes, we have defined a pivotal trial as a study that was extensively relied on by the agency for approval purposes. This means extensive discussion in regulatory materials surrounding the approval and, generally, inclusion on the approved prescribing label.) As shown in Figure 1, 60% percent of approved indications were for solid tumors while the remaining 40% were for hematologic malignancies. Of 22 different conditions with approvals, leukemia, breast cancer, and Non-Hodgkin lymphoma saw the highest level of activity; together, these three cancers represented over one-third of all drugs approved during the period. Forty-one percent of all approvals had previously received orphan drug designation. Although more approvals were for solid tumors, the majority of orphan drug indications were for hematologic malignancies.

Figure 1- Cancer Drug Approvals by Cancer Type 2005-2011

The rapid advance in cancer research is clearly evident in Figure 2. As shown, traditional anti-cancer agents such as chemotherapeutics and hormonal drugs accounted for two-thirds of approvals in 2005. By 2011 this had shrunk to less than 15% as new generation treatments such as biologics, targeted oral drugs, and vaccines have come to dominate the field. Although not shown on the chart, the trend towards new generation therapies has been driven mostly by the kinase inhibitor class. The first of these therapies, imatinib, was approved just a little over ten years ago but the category, which also includes erlotinib, nilotinib, sutininib, and several others, accounted for one-third of all approved indications over our total time period and reached 50% of all approvals in 2011.

Figure 2 - Approvals by Drug Type 2005-2011

2011 – Highest Level of FDA New Drug Approval since 2004

The just published annual FDA review from Nature Reviews Drug Discovery finds a rebound in new drug approvals. With 24 new molecular entities and six new biologics receiving first-time marketing clearance, 2011 was the most active year since 2004 when 31 NMEs and five biologics were approved. The trend towards narrowly-focused therapeutic categories continued with 11 of the new drugs being designated as orphan drugs. Cancer was the single largest area of activity, representing 35% of approvals, the majority of these were also orphan drugs. Nonetheless, the fading blockbuster categories also showed some life as hypertension, major depressive disorder, and Type 2 diabetes each saw a single new approval.In part, the 2011 upswing is attributed to a higher success rate for applications. The FDA has approved half of applications in recent years but last year the rate improved to over 80%. It seems likely that there will be some reversion to the mean in 2012 but one can hope that improvements in trial design, submissions, and perhaps also in regulatory attitudes might sustain the trend to some degree going forward.

Therapeutic Cancer Vaccines Webinar

Todd Clark, President of VOI Consulting, will be participating in a webcast hosted by Clinipace Worldwide on Tuesday, December 6, 2011 at 2:00 pm EST. The webcast, “Game Plan for Therapeutic Cancer Vaccines,” will address the nuances of clinical trials in the rapidly growing field of cancer vaccines. Using findings from  VOI’s new insiteinvestigator database, Todd will be covering aspects related to the size, location, timing, and accrual of vaccines trials and how these factors compare to trials of other cancer drugs. Registration is free and can be accessed at http://clinipace.com/webcast-game-plan-for-therapeutic-cancer-vaccines.htm.