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FDA Update on Provisional Substantial Equivalence (SE) Review Process

Web Statement – April 5, 2018

Since the Family Smoking Prevention and Tobacco Control Act (TCA) was signed in 2009, FDA’s Center for Tobacco Products (CTP) has been responsible for using the tools of product regulation to help reduce the disease and death associated with tobacco use in the United States. As part of that effort, the agency is reviewing applications for new tobacco products and monitoring which tobacco products can be sold and distributed on the market in accordance with the law.

To accomplish those goals, FDA has created processes and enacted policies implementing the statute to generate the greatest positive impact on public health. Today, FDA is announcing a change in its process for reviewing the marketing SE Reports for a subset of tobacco products – known as “provisional substantial equivalence tobacco products” – that have been provisionally permitted to be sold on the market since 2011.

Having now gained years of experience reviewing thousands of SE Reports, FDA’s new approach will allow FDA to better utilize its resources while continuing to protect the public health. To understand FDA’s new approach – and how the agency arrived at this change – it is helpful to know the history of these products.

Creation of the SE Program and the Provisional Period (2009-2011)

When the TCA went into effect in 2009, it established several pathways for new tobacco products to obtain premarket authorization; to date, SE is the most commonly used pathway. The essence of the SE pathway is that a manufacturer submits an application comparing the new tobacco product it wishes to bring to market to a valid predicate tobacco product. New tobacco products subject to SE Reports received by FDA after March 22, 2011 cannot be legally sold or marketed unless FDA issues an SE order. FDA refers to these types of applications as “regular” SE Reports.

The TCA also stated that tobacco products introduced into commercial distribution after February 15, 2007 – but before March 22, 2011 – could remain on the market if they were the subject of an SE Report submitted no later than March 22, 2011. A new tobacco product that meets both of these criteria can be legally marketed unless FDA issues a not substantially equivalent (NSE) order. By March 22, 2011, FDA had received nearly 3,600 applications that were classified as “provisional SE Reports” – nearly all of which were submitted within the final few days before the deadline.

In both cases – provisional and regular SE Reports – the manufacturer must demonstrate that the new product has the same characteristics as the predicate product, or if it has different characteristics, that those differences do not cause the new tobacco product to raise different questions of public health.

Building the SE Program and Prioritizing Review (2011-2013)

Because these review processes – and CTP itself – were newly created, FDA developed internal processes for reviewing all of the SE applications submitted. Although FDA is not required by statute to review or act on the provisional SE Reports, the agency initially intended to review and act on all of them. To do so, FDA triaged the review of provisional tobacco products based upon an initial public health impact (PHI) assessment conducted in 2013.

The assessment was used to determine the review order of the provisional products and prioritized review of new tobacco products that had different characteristics as compared to the predicate, where such differences had the greatest potential to cause the new tobacco product to raise different questions of public health. Scientific review for the provisional tobacco products that had the greatest potential to raise different questions of public health began in spring 2013.

Over the years, FDA continued to develop and improve processes for how it would review and issue decisions on SE Reports. In 2013, FDA issued its first decisions for tobacco products submitted via regular SE applications.

Making Progress and Gaining Experience (2013-2017)

Since the first decisions were issued in 2013, the agency has reviewed and resolved thousands of SE applications for new tobacco products not yet on the market. In total, FDA has received more than 2,500 regular SE submissions and resolved 93 percent of them, including issuing 601 SE orders, 202 NSE orders, and 288 Refuse-To-Accepts. Those that received SE orders met the law’s requirements, while hundreds of new tobacco products – through NSE orders and Refusal-To-Accept – were prevented from being introduced to the market because they didn’t meet the public health standard set forth in the law or the requirements to properly submit applications. Nearly 900 additional products also were never introduced to the market because their applications were withdrawn by the manufacturer; it is likely that many of these applications were withdrawn because the manufacturer expected the tobacco product would receive an NSE order.1

FDA also continued to take action and resolve provisional SE applications. Of the nearly 3,600 provisional SE applications submitted, FDA has resolved over 1,000 of them, including issuing 107 SE orders, 14 Refusal-to-Accepts, 847 withdrawals, 23 cancellations, and 84 NSE orders. As a result, manufacturers could no longer legally sell or distribute those 84 products that received an NSE order.2

During this period, CTP’s Office of Science expanded in size and gained knowledge from review of thousands of SE applications. This experience has increased FDA’s understanding of tobacco products and their public health impact. With time, tobacco manufacturers were also able to improve the quality of the applications they submitted.

Currently, 99 percent of acceptance reviews (to determine whether a product is under CTP’s jurisdiction and that the application includes required items) for the remaining regular SE Reports have been completed, and performance measures have been put in place and tracked for several years. Furthermore, there is no backlog of new regular SE applications; since March 2014, review of new SE applications begins upon FDA receipt.

A New Approach (2018)

In July 2017, FDA Commissioner Scott Gottlieb, M.D. announced a new comprehensive plan for tobacco regulation. As part of the announcement, Commissioner Gottlieb noted CTP would examine its existing approach to the review of the approximately 2,500 remaining provisional SE Reports.

With the years of experience conducting thousands of SE reviews, and with a greater understanding of tobacco products, FDA is announcing a change in its approach: The agency will continue to review the approximately 1,000 pending provisional SE Reports that were determined to have the greatest potential to raise different questions of public health and will remove from review the approximately 1,500 provisional SE Reports that were determined less likely to do so.

FDA assessed a host of factors to determine which new tobacco products subject to provisional SE Reports had the greatest potential to raise different questions of public health, including, for example, whether the new product had a significant increase in any harmful and potentially harmful constituents compared to the predicate product.

The approximately 1,000 provisional SE Reports determined to have the greatest potential to raise different questions of public health will undergo full multi-disciplinary scientific review by FDA and maintain their provisional status until FDA issues an order; the agency has already begun review for more than 675 of these and intends to continue issuing notification letters letting manufacturers know the scientific review process has begun.

Since Fiscal Year (FY) 2015, FDA has tracked its performance measures for regular SE, Exemption from SE and Modified Risk Tobacco Product applications on its website. Now, for the first time, FDA is also establishing performance measures for the review of the remaining provisional SE Reports in the queue. Starting in FY19, FDA intends to meet the following goals for the review of all remaining provisional SE Reports:

Performance Measure FY19 Goal GY20 Goal FY21 Goal FY22 Goal
Issue Withdrawal Acknowledgment letter within 21 days of receiving Withdrawal Request 50% 60% 70% 80%
Issue Advice/Information letter, Preliminary Finding letter, Cancellation, Closure, SE Order, or NSE Order within 120 days of scientific review commencing 50% 60% 70% 80%

FDA’s progress in meeting these goals will be updated at the end of each fiscal year. The establishment of these performance measures will guide FDA’s efforts and will allow for all interested stakeholders to stay up-to-date on progress in reviewing these SE Reports. 

The remaining provisional SE Reports, of which there are approximately 1,500, are being removed from review because these products were determined to have a lower potential to raise different questions of public health. For example, many of these provisional SE Reports are for cigarettes where the only change is a switch to fire standard compliant cigarette paper.

Our regulatory health project managers are making courtesy calls and sending letters throughout the day to manufacturers of the products being removed from review. Having been removed from review does not change the legal marketing status of these tobacco products and these products cannot serve as valid predicate products for a new SE application3. The products removed from review can be legally marketed but will be returned to the review queue if one or more of the following criteria is met:

  • The provisional SE product is also the subject of another pending application submitted by the same manufacturer through certain other pathways (i.e., an MRTP application, SE application , or an Exemption from SE Request);
  • FDA receives new information suggesting that the provisional SE product is more likely to have the potential to raise different questions of public health than previously determined (e.g., inspectional findings); or
  • FDA has reason to believe that the provisional tobacco product was not introduced or delivered for introduction into interstate commerce for commercial distribution in the United States after February 15, 2007, and prior to March 22, 2011.

This new approach to the provisional SE queue will allow for increased efficiency, better use of resources, and greater transparency. By removing certain products from review and holding ourselves to new goals for resolving the remaining SE Reports, FDA will be able to address provisional SE Reports awaiting review, and in turn, better serve the public interest.

Providing Informational Materials

As part of making the SE review process efficient, applicants need to submit clear and complete SE applications. To that end, FDA’s website offers a number of resources – including guidances, webinars, frequently asked questions, redacted SE and provisional NSE summaries, and a summary of the review process – for companies to view to inform their applications.

FDA also intends to issue an SE proposed rule, which – when final – would set specific requirements for the content and format of SE applications, ultimately helping to limit the back and forth between FDA and applicants. All of these measures will be supported by increased efforts via the web and social media to highlight and promote the many SE-related resources.

Using Resources Effectively to Protect Public Health

As Commissioner Gottlieb noted in July, it is in the best interest of all parties for FDA to use its resources most effectively. Removing these products from review will help FDA carry out its public health mission. Doing so doesn’t require the use of resources to carry out full multi-discipline scientific reviews when FDA has already determined these products are less likely to raise different questions of public health.

After more than seven years of growth as an institution and extensive experience with SE reviews of cigarettes, smokeless tobacco products, and roll-your-own tobacco products, FDA expects that this updated approach will allow the agency to better serve the public interest and carry out its statutory mission moving forward by concentrating only on those provisional products which, based on the information submitted, are most likely to raise different questions of public health.

The scientific review of tobacco products is one of the most important ways FDA protects the public health from the harms associated with tobacco use. FDA remains dedicated to upholding the standards set forth in the law for the premarket review of tobacco products, and will continue to efficiently review products, issue decisions, and update the public on its progress.

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