{"id":40013,"date":"2026-10-29T09:47:00","date_gmt":"2026-10-29T13:47:00","guid":{"rendered":"https:\/\/www.drugpatentwatch.com\/blog\/?p=40013"},"modified":"2026-10-26T15:51:22","modified_gmt":"2026-10-26T19:51:22","slug":"the-second-source-clock-starts-before-the-patent-cliff","status":"publish","type":"post","link":"https:\/\/www.drugpatentwatch.com\/blog\/the-second-source-clock-starts-before-the-patent-cliff\/","title":{"rendered":"The Second-Source Clock Starts Before the Patent Cliff"},"content":{"rendered":"\n<figure class=\"wp-block-image size-full\"><img loading=\"lazy\" decoding=\"async\" width=\"1024\" height=\"572\" src=\"https:\/\/www.drugpatentwatch.com\/blog\/wp-content\/uploads\/2026\/10\/image-26.png\" alt=\"\" class=\"wp-image-40014\" srcset=\"https:\/\/www.drugpatentwatch.com\/blog\/wp-content\/uploads\/2026\/10\/image-26.png 1024w, https:\/\/www.drugpatentwatch.com\/blog\/wp-content\/uploads\/2026\/10\/image-26-300x168.png 300w, https:\/\/www.drugpatentwatch.com\/blog\/wp-content\/uploads\/2026\/10\/image-26-768x429.png 768w\" sizes=\"auto, (max-width: 1024px) 100vw, 1024px\" \/><\/figure>\n\n\n\n<p class=\"wp-block-paragraph\">The first generic Entresto reached US pharmacies on July 22, 2025. <a href=\"#ref-1\">[1]<\/a> Novartis had said in 2023 that the combination patent, with its pediatric exclusivity, would expire on July 15, 2025. <a href=\"#ref-2\">[2]<\/a> The gap between the two dates was seven days (our calculation).<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Novartis reported Entresto net sales of USD 1,253 million for the fourth quarter of 2025. That is 43% lower than the same quarter of 2024 in US dollars. <a href=\"#ref-3\">[3]<\/a> Sales fell in weeks. A new drug substance supplier cannot be qualified in weeks.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">This article explains why a company that starts to qualify a second source at the patent cliff starts too late. We use FDA rules, FDA review goals, FDA price data, company filings and four real supply events. We also give a lead-time model with stated assumptions. DrugPatentWatch is one place to find the expiry dates that start the clock. <a href=\"#ref-4\">[4]<\/a><\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>The Short Answer<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">Qualifying a second source takes 14 to 28 months in our model. The loss-of-exclusivity (LOE) date is public years before it arrives. Novartis published the Entresto expiry date about two years before it happened. <a href=\"#ref-2\">[2]<\/a> A company that starts at the cliff gets FDA action in the second or third year of generic competition, after prices have fallen.<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>FDA says an alternate drug substance source for an ANDA should be reported in a prior approval supplement (PAS). <a href=\"#ref-5\">[5]<\/a><\/li>\n\n\n\n<li>The FDA goal under GDUFA III is to act on 90% of standard PASs within 6 months, or within 10 months if a preapproval inspection is required. <a href=\"#ref-6\">[6]<\/a><\/li>\n\n\n\n<li>FDA asks for at least 3 months of long-term and 3 months of accelerated drug product stability data for an alternate API source. <a href=\"#ref-5\">[5]<\/a><\/li>\n\n\n\n<li>In FDA data on first generic entry from 2015 to 2017, the median invoice-based generic price fell to 27% of the brand price when four generic producers were present. <a href=\"#ref-7\">[7]<\/a><\/li>\n<\/ul>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>What the Data Shows: Eight Findings You Can Cite<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">Each finding stands alone. We label calculated figures as analysis. We do not present them as reported statistics.<\/p>\n\n\n\n<ol class=\"wp-block-list\">\n<li>FDA classifies an alternate drug substance source for an ANDA as a PAS. The one listed exception is a changes-being-effected-in-30-days supplement (CBE-30) for the same applicant&#8217;s other products, when that source already has PAS approval. <a href=\"#ref-5\">[5]<\/a><\/li>\n\n\n\n<li>The GDUFA III goal for a standard PAS is 6 months without a preapproval inspection and 10 months with one. The priority goal is 4 months, or 8 months with an inspection when the applicant meets the pre-submission facility correspondence conditions. <a href=\"#ref-6\">[6]<\/a><\/li>\n\n\n\n<li>A lead-time model built from FDA goals and stated assumptions gives 14, 19 and 28 months from the start of qualification to FDA action (analysis).<\/li>\n\n\n\n<li>The first generic Entresto launched seven days after the combination patent expired (analysis). Entresto net sales fell 43% in US dollars in the fourth quarter of 2025. <a href=\"#ref-1\">[1]<\/a><a href=\"#ref-2\">[2]<\/a><a href=\"#ref-3\">[3]<\/a><\/li>\n\n\n\n<li>In FDA data, the median invoice-based generic price ratio fell from 0.696 with one generic producer to 0.268 with four. That is 62% lower (analysis). <a href=\"#ref-7\">[7]<\/a><\/li>\n\n\n\n<li>In IQVIA data on products that gained generic competition from 2002 to 2014, oral medicine prices fell 66% in the first year and 74% in the second year. <a href=\"#ref-8\">[8]<\/a><\/li>\n\n\n\n<li>ASHP and the University of Utah counted 227 active US drug shortages in the second quarter of 2026. That was the third quarterly increase in a row. <a href=\"#ref-9\">[9]<\/a><\/li>\n\n\n\n<li>FDA approved a new generic valsartan on March 13, 2019. The recalls had started in July 2018. The gap is about eight months (analysis). <a href=\"#ref-10\">[10]<\/a><\/li>\n<\/ol>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>What Is a Second-Source Supplier in Pharmaceutical Manufacturing?<\/strong><\/h2>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Definitions: Second Source, Loss of Exclusivity and Patent Cliff<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">A second source is a supplier or site that FDA has cleared for a material or an operation, in addition to the first supplier. The first supplier is the primary source.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Loss of exclusivity (LOE) is the date when the last patent or regulatory exclusivity that blocks generic entry ends. The patent cliff is the sharp fall in sales that follows LOE.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">A prior approval supplement (PAS) is a change submission that FDA must approve before the applicant distributes product made with the change. <a href=\"#ref-11\">[11]<\/a> A CBE-30 is a supplement that lets distribution begin not less than 30 days after FDA receives it. <a href=\"#ref-11\">[11]<\/a><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Pre-submission facility correspondence (PFC) is information about the manufacturing sites that the applicant sends before the supplement. Under GDUFA III, a complete and accurate PFC sent at least 60 days before a priority PAS qualifies the applicant for the 8-month inspection goal. <a href=\"#ref-6\">[6]<\/a><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Tentative approval is an FDA decision that an ANDA meets the approval requirements but that a patent or exclusivity blocks final approval.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>A Four-Type Taxonomy of Second Sources (Original Framework)<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">This framework is ours. It is not an FDA classification. It groups second sources by the filing that each one triggers.<\/p>\n\n\n\n<figure class=\"wp-block-table\"><table class=\"has-fixed-layout\"><thead><tr><th>Type<\/th><th>What changes<\/th><th>Typical FDA filing<\/th><th>Source<\/th><\/tr><\/thead><tbody><tr><td>Type 1<\/td><td>New drug substance (API) manufacturer<\/td><td>PAS for an ANDA<\/td><td><a href=\"#ref-5\">[5]<\/a><\/td><\/tr><tr><td>Type 2<\/td><td>New drug product manufacturing site<\/td><td>PAS if FDA never inspected the site for that operation; CBE-30 if the site has current GMP status for the operation<\/td><td><a href=\"#ref-12\">[12]<\/a><\/td><\/tr><tr><td>Type 3<\/td><td>New site for the final intermediate, or for an earlier intermediate<\/td><td>CBE for the final intermediate; annual report for earlier intermediates<\/td><td><a href=\"#ref-13\">[13]<\/a><\/td><\/tr><tr><td>Type 4<\/td><td>New container closure or packaging component that affects the delivered product or the impurity profile<\/td><td>PAS<\/td><td><a href=\"#ref-11\">[11]<\/a><\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<h4 class=\"wp-block-heading\"><strong>Why Type 1 Has the Longest Lead Time<\/strong><\/h4>\n\n\n\n<p class=\"wp-block-paragraph\">FDA states that a switch of drug substance manufacturer is more than a site change. The route of synthesis, the process, the solvents and the equipment usually differ. <a href=\"#ref-5\">[5]<\/a> FDA also lists a change in the route of synthesis as a major change for a drug substance. <a href=\"#ref-13\">[13]<\/a> Each difference adds work for the applicant before the filing and review work for FDA after it.<\/p>\n\n\n\n<h4 class=\"wp-block-heading\"><strong>Why Type 2 Is Different<\/strong><\/h4>\n\n\n\n<p class=\"wp-block-paragraph\">A drug product site that FDA already inspected for the same operation can move through a CBE-30. <a href=\"#ref-12\">[12]<\/a> A new API manufacturer has no such shortcut in the FDA presentation we reviewed. That is why this article focuses on Type 1.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>How Does FDA Classify a New API Supplier Change?<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">For an ANDA, FDA says the applicant should report an alternate drug substance source in a prior approval supplement. <a href=\"#ref-5\">[5]<\/a> The applicant cannot distribute product made with the new source until FDA approves the supplement. <a href=\"#ref-11\">[11]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>The Four Reporting Categories Under 21 CFR 314.70<\/strong><\/h3>\n\n\n\n<figure class=\"wp-block-table\"><table class=\"has-fixed-layout\"><thead><tr><th>Category<\/th><th>Level of risk<\/th><th>Rule<\/th><th>Source<\/th><\/tr><\/thead><tbody><tr><td>Prior approval supplement<\/td><td>Substantial potential to affect identity, strength, quality, purity or potency<\/td><td>Approval before distribution<\/td><td><a href=\"#ref-11\">[11]<\/a><\/td><\/tr><tr><td>CBE-30<\/td><td>Moderate potential<\/td><td>Distribution not less than 30 days after FDA receives the supplement<\/td><td><a href=\"#ref-11\">[11]<\/a><\/td><\/tr><tr><td>Changes being effected (CBE)<\/td><td>Categories that FDA designates<\/td><td>Distribution on receipt of the supplement<\/td><td><a href=\"#ref-11\">[11]<\/a><\/td><\/tr><tr><td>Annual report<\/td><td>Minimal potential<\/td><td>Description in the next annual report<\/td><td><a href=\"#ref-11\">[11]<\/a><\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<p class=\"wp-block-paragraph\">The regulation lists examples of major changes. One example is a change that may affect the impurity profile or the properties of the drug substance. <a href=\"#ref-11\">[11]<\/a> A new API manufacturer fits that description.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>What Does FDA Say About an Alternate Drug Substance Source?<\/strong><\/h3>\n\n\n\n<h4 class=\"wp-block-heading\"><strong>Why FDA Treats a New Source as a PAS<\/strong><\/h4>\n\n\n\n<p class=\"wp-block-paragraph\">An FDA quality reviewer presentation from April 2023 says a new drug substance source has a high potential to affect the impurity profile of the drug substance. <a href=\"#ref-5\">[5]<\/a> That risk puts the change in the major category.<\/p>\n\n\n\n<h4 class=\"wp-block-heading\"><strong>The Single CBE-30 Exception<\/strong><\/h4>\n\n\n\n<p class=\"wp-block-paragraph\">The presentation gives one exception. An applicant can report the same alternate source for its other drug products as a CBE-30. This works only when the same applicant already has that source approved as a PAS in another ANDA. The other products must have no PAS-type changes, and the API sites must have satisfactory CGMP inspection status. <a href=\"#ref-5\">[5]<\/a><\/p>\n\n\n\n<h4 class=\"wp-block-heading\"><strong>What Data the Supplement Needs<\/strong><\/h4>\n\n\n\n<p class=\"wp-block-paragraph\">The same presentation lists the data package for an alternate API source. <a href=\"#ref-5\">[5]<\/a><\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>A comparison and justification of comparability, including physicochemical properties and impurities.<\/li>\n\n\n\n<li>Certificates of analysis from the drug substance manufacturer and from the drug product manufacturer.<\/li>\n\n\n\n<li>At least one pilot-scale or commercial-scale drug product batch made with the alternate source.<\/li>\n\n\n\n<li>A minimum of 3 months of long-term and 3 months of accelerated drug product stability data.<\/li>\n\n\n\n<li>Comparative dissolution data. FDA says the change is supported when comparative dissolution is similar.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Does the Same Rule Apply to NDA Holders?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">The FDA presentation covers pending ANDAs and ANDA supplements. It does not address NDAs. <a href=\"#ref-5\">[5]<\/a> NDA holders still follow 21 CFR 314.70, which classes a change that may affect the impurity profile of a drug substance as major. <a href=\"#ref-11\">[11]<\/a> The 2004 FDA guidance on changes to an approved NDA or ANDA covers both application types. It lists a change in the route of synthesis, and any process change after the final intermediate step, as major changes. <a href=\"#ref-13\">[13]<\/a><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">An NDA holder that plans a new API source should classify the change under both documents. The holder should then confirm the category with FDA before it plans the timeline.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>How Long Does Second-Source Qualification Take? A Lead-Time Model<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">The model gives 14, 19 or 28 months from the start of work to FDA action. About two thirds of that time is work that the applicant controls.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Model Design and Assumptions<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">We modeled a Type 1 change. An ANDA holder adds a second API manufacturer for an approved product. The model has three phases.<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Phase A: supplier selection, technology transfer and API process validation. We assume 6, 9 or 12 months. FDA sets no goal for this phase.<\/li>\n\n\n\n<li>Phase B: a drug product batch made with the new API, plus stability data. FDA asks for at least 3 months of data. <a href=\"#ref-5\">[5]<\/a> We assume 1 month to make and test the batch. We assume 6 months of data in the slow case.<\/li>\n\n\n\n<li>Phase C: FDA review of the PAS. We use the GDUFA III goals of 4, 6 and 10 months. <a href=\"#ref-6\">[6]<\/a><\/li>\n<\/ul>\n\n\n\n<p class=\"wp-block-paragraph\">We run the phases one after the other. Real programs can overlap them. The PFC, for example, goes to FDA at least 60 days before the supplement. <a href=\"#ref-6\">[6]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Results: 14, 19 or 28 Months<\/strong><\/h3>\n\n\n\n<figure class=\"wp-block-table\"><table class=\"has-fixed-layout\"><thead><tr><th>Phase<\/th><th>Fast case<\/th><th>Standard case<\/th><th>Slow case<\/th><th>Basis<\/th><\/tr><\/thead><tbody><tr><td>A. Supplier selection, transfer and API validation<\/td><td>6 months<\/td><td>9 months<\/td><td>12 months<\/td><td>Our assumption<\/td><\/tr><tr><td>B. Drug product batch and stability data<\/td><td>4 months<\/td><td>4 months<\/td><td>6 months<\/td><td>3-month FDA minimum <a href=\"#ref-5\">[5]<\/a>; remainder is our assumption<\/td><\/tr><tr><td>C. FDA review of the PAS<\/td><td>4 months<\/td><td>6 months<\/td><td>10 months<\/td><td>GDUFA III goals <a href=\"#ref-6\">[6]<\/a><\/td><\/tr><tr><td>Total to FDA action<\/td><td>14 months<\/td><td>19 months<\/td><td>28 months<\/td><td>Analysis<\/td><\/tr><tr><td>Total with one added review cycle of 6 months<\/td><td>20 months<\/td><td>25 months<\/td><td>34 months<\/td><td>Analysis; the 6-month cycle is our assumption<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<p class=\"wp-block-paragraph\">The fast case needs a priority PAS with no preapproval inspection. The standard case uses a standard PAS with no inspection. The slow case needs an inspection and uses the 10-month goal.<\/p>\n\n\n\n<h4 class=\"wp-block-heading\"><strong>What the Review Goal Does to the Total<\/strong><\/h4>\n\n\n\n<p class=\"wp-block-paragraph\">FDA review is 4 of 14 months in the fast case (29%). It is 6 of 19 months in the standard case (32%). It is 10 of 28 months in the slow case (36%). The rest of each total is work that the applicant controls (analysis).<\/p>\n\n\n\n<h4 class=\"wp-block-heading\"><strong>Sensitivity: One More Review Cycle<\/strong><\/h4>\n\n\n\n<p class=\"wp-block-paragraph\">An FDA action on the goal date can be a complete response letter instead of an approval. We assume one more review cycle of 6 months. The totals then rise to 20, 25 and 34 months. We do not know the share of PASs that need a second cycle. We do not model that share.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>What FDA&#8217;s FY2025 Data Shows About Review Performance<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">The FDA fiscal year 2025 generic drugs activities report lists 1,685 standard PASs without a preapproval inspection. FDA had completed actions on 973 of them, and 99% of those actions met the 6-month goal. <a href=\"#ref-14\">[14]<\/a><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">The report lists 25 standard PASs that needed an inspection. FDA had completed 6, all on time. It lists 118 priority PASs without an inspection. FDA had completed 89, and 96% were on time. <a href=\"#ref-14\">[14]<\/a><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">These figures measure timeliness of FDA action. They do not measure the share of approvals.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Can FDA Speed Up a Supplement During a Shortage?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">Yes, an applicant can ask for it. An FDA division director said in a 2015 presentation that an applicant may request expedited review for a public health need, such as a drug shortage. <a href=\"#ref-12\">[12]<\/a><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Expedited review does not remove Phases A and B. The valsartan case shows the limit. FDA said it prioritized review of generic valsartan applications. The new generic still came about eight months after the recalls began. <a href=\"#ref-10\">[10]<\/a><\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>When Does the Patent Cliff Become Visible?<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">The cliff becomes visible years ahead. Patent terms, regulatory exclusivities and litigation outcomes are public records. Company statements add dates.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Where Do Cliff Dates Come From?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">The main records are the FDA Orange Book, USPTO patent data, court dockets and company filings. DrugPatentWatch says on its home page that it pulls from the USPTO, the FDA Orange Book, ANDA filings and litigation records. The page also lists patent expiry opportunities for 2025 to 2030. <a href=\"#ref-4\">[4]<\/a> We recommend that you verify any aggregator date against the primary record.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>How Large Is the Cliff? A Third-Party Estimate<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">Evaluate estimates that more than USD 300 billion of global prescription drug revenue loses exclusivity from 2025 to 2030. IntuitionLabs reports this figure. A second estimate in the same report, from GlobalData, covers only the US and gives over USD 230 billion. The report warns that figures from different firms use different scopes and methods. <a href=\"#ref-15\">[15]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Why Is the Cliff Date a Range?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">The Entresto case shows how the date moves. The 2023 Novartis release gave July 15, 2025 for the combination patent with pediatric exclusivity. The same release said other Entresto patents, expiring from 2026 to 2036, were in separate litigation. It also said Novartis had settled with several ANDA filers who could launch on an agreed date. Novartis did not disclose that date. <a href=\"#ref-2\">[2]<\/a><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">In August 2024, the US District Court for the District of Delaware denied Novartis a preliminary injunction against MSN Pharmaceuticals. The motion relied on US Patent No. 11,096,918. <a href=\"#ref-16\">[16]<\/a> A supply team that planned only to July 15, 2025 would have missed the risk of earlier entry.<\/p>\n\n\n\n<h4 class=\"wp-block-heading\"><strong>A Planning Rule: Use the Earliest Credible Entry Date<\/strong><\/h4>\n\n\n\n<p class=\"wp-block-paragraph\">We recommend that you plan to the earliest date that litigation, settlement or regulatory records can support. You can move the plan later. You cannot add months to a lead time that has already run.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>Case Study: Entresto (Sacubitril\/Valsartan) and the Seven-Day Cliff<\/strong><\/h2>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Entresto Timeline, 2023 to 2026<\/strong><\/h3>\n\n\n\n<figure class=\"wp-block-table\"><table class=\"has-fixed-layout\"><thead><tr><th>Date<\/th><th>Event<\/th><th>Source<\/th><\/tr><\/thead><tbody><tr><td>July 7, 2023<\/td><td>Novartis states that US Patent No. 8,101,659, with pediatric exclusivity, expires July 15, 2025. No generic has tentative or final approval.<\/td><td><a href=\"#ref-2\">[2]<\/a><\/td><\/tr><tr><td>July 2024<\/td><td>MSN receives final FDA approval for a generic sacubitril\/valsartan.<\/td><td><a href=\"#ref-16\">[16]<\/a><\/td><\/tr><tr><td>August 12, 2024<\/td><td>The District of Delaware denies Novartis a preliminary injunction against MSN on US Patent No. 11,096,918.<\/td><td><a href=\"#ref-16\">[16]<\/a><\/td><\/tr><tr><td>July 15, 2025<\/td><td>The &#8216;659 patent and its pediatric exclusivity expire.<\/td><td><a href=\"#ref-2\">[2]<\/a><\/td><\/tr><tr><td>July 22, 2025<\/td><td>Novadoz launches the AB-rated generic made by MSN.<\/td><td><a href=\"#ref-1\">[1]<\/a><\/td><\/tr><tr><td>July 24, 2025<\/td><td>Torrent launches its generic.<\/td><td><a href=\"#ref-1\">[1]<\/a><\/td><\/tr><tr><td>Q3 2025<\/td><td>Entresto net sales are USD 1,877 million, up 1% in US dollars. Novartis reports a US decline where generics launched.<\/td><td><a href=\"#ref-17\">[17]<\/a><\/td><\/tr><tr><td>Q4 2025<\/td><td>Net sales are USD 1,253 million, down 43% in US dollars.<\/td><td><a href=\"#ref-3\">[3]<\/a><\/td><\/tr><tr><td>Full year 2025<\/td><td>Net sales are USD 7,748 million, against USD 7,822 million in 2024 (down 1%).<\/td><td><a href=\"#ref-3\">[3]<\/a><\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<h4 class=\"wp-block-heading\"><strong>Twelve Months of Generic Readiness<\/strong><\/h4>\n\n\n\n<p class=\"wp-block-paragraph\">MSN received final FDA approval in July 2024. Its product launched on July 22, 2025. <a href=\"#ref-16\">[16]<\/a><a href=\"#ref-1\">[1]<\/a> The interval is about 12 months (analysis; the source gives the approval month only). The patent date, not FDA, set the launch date. A generic company with an approved product waited for the patent date. A company without a qualified supply chain could not have used that wait.<\/p>\n\n\n\n<h4 class=\"wp-block-heading\"><strong>What Happened to Entresto Sales<\/strong><\/h4>\n\n\n\n<p class=\"wp-block-paragraph\">Fourth-quarter sales were 33% lower than third-quarter sales (analysis: (1,253 &#8211; 1,877) \/ 1,877). The fourth quarter produced 16% of full-year 2025 sales (analysis: 1,253 \/ 7,748). A quarter at the annual average would have produced 25%.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Full-year sales fell only 1% because the first nine months grew. Nine-month sales were USD 6,495 million, up 15%. <a href=\"#ref-17\">[17]<\/a> Novartis also said that revenue deduction adjustments affected US performance in the fourth quarter. Without those adjustments, the fourth-quarter decline was 32% in US dollars. Novartis said Entresto kept growing outside the US. <a href=\"#ref-3\">[3]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>What the Lead-Time Model Says About Entresto<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">We applied the model to the public July 15, 2025 date. We do not know the supplier arrangements of Novartis or of any generic company. The table is an illustration, not a statement about any company.<\/p>\n\n\n\n<figure class=\"wp-block-table\"><table class=\"has-fixed-layout\"><thead><tr><th>Model case<\/th><th>Months of lead time<\/th><th>Latest start date for FDA action by July 15, 2025<\/th><th>FDA action if work starts on July 15, 2025<\/th><\/tr><\/thead><tbody><tr><td>Fast<\/td><td>14<\/td><td>May 15, 2024<\/td><td>September 15, 2026<\/td><\/tr><tr><td>Standard<\/td><td>19<\/td><td>December 15, 2023<\/td><td>February 15, 2027<\/td><\/tr><tr><td>Slow<\/td><td>28<\/td><td>March 15, 2023<\/td><td>November 15, 2027<\/td><\/tr><tr><td>Slow, one added review cycle<\/td><td>34<\/td><td>September 15, 2022<\/td><td>May 15, 2028<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<p class=\"wp-block-paragraph\">The Novartis release of July 7, 2023 is later than the start dates for the slow cases. A supplier program that began after that release could not have finished by the expiry date in the slow cases.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>Case Study: Revlimid (Lenalidomide) and the Scheduled Volume Cap<\/strong><\/h2>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>How Did Volume-Limited Generic Entry Work for Revlimid?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">I-MAK, a patent-reform nonprofit, reports that settling generic companies could take no more than 7% of the total market from early 2022. It reports that generic sales without restriction start only in January 2026. <a href=\"#ref-18\">[18]<\/a> We did not verify the settlement terms against the settlement documents. We treat I-MAK as a secondary source.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">If the I-MAK dates are right, the schedule gave suppliers about four years of notice (analysis). Nobody had to guess the LOE date. Every supplier could count back from January 2026.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>What Did Revlimid Revenue Do After the Schedule Ended?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">Bristol Myers Squibb reported global Revlimid revenue of USD 425 million for the second quarter of 2026. The figure for the second quarter of 2025 was USD 838 million. <a href=\"#ref-19\">[19]<\/a> That is a 49.3% decline (analysis). For the first six months, revenue was USD 773 million in 2026 and USD 1,774 million in 2025, a 56.4% decline (analysis). <a href=\"#ref-19\">[19]<\/a><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">The lesson for supply planning is simple. A capped schedule turns a cliff into a ramp, and the ramp is known in advance. A company that wants a share of that ramp needs an approved supply chain on the first day of each stage.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>Case Study: Valsartan Recalls, July 2018 to March 2019<\/strong><\/h2>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>One API Supplier, Many Finished-Dose Companies<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">On August 30, 2018, FDA said the valsartan recall had grown to five manufacturers and other companies. Zhejiang Huahai Pharmaceutical was the API supplier to Prinston Pharmaceuticals. More than half of valsartan products were under recall. <a href=\"#ref-20\">[20]<\/a> Recalling companies included Major Pharmaceuticals, Teva, Solco Healthcare, Mylan, Aurobindo and Torrent. <a href=\"#ref-10\">[10]<\/a><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">The brand product Diovan was not recalled. <a href=\"#ref-10\">[10]<\/a> The event started as an impurity problem. We include it because it shows what a shared API source costs a market after generic entry.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>How Long Did FDA Take to Approve a Replacement?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">FDA approved a new generic valsartan from Alkem Laboratories on March 13, 2019. Commissioner Scott Gottlieb said FDA had &#8216;prioritized the review of generic applications for these valsartan products.&#8217; <a href=\"#ref-10\">[10]<\/a> The recalls began in July 2018. The interval is about eight months (analysis).<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Eight months is shorter than any case in our lead-time model. It is also a new generic approval and not a PAS. The case shows that FDA priority does not remove the time needed to prepare and submit a complete application.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>Case Study: Cisplatin and Carboplatin Shortages in 2023<\/strong><\/h2>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>What Happened at the Intas Plant?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">CNBC reported in June 2023 that cisplatin and carboplatin were the most acute of at least 14 cancer drugs in shortage. Intas Pharmaceuticals, based in Ahmedabad, India, sells in the US through Accord Healthcare. It stopped making the drugs for the US market after an FDA inspection found a &#8216;cascade of failure&#8217; in its quality control unit. <a href=\"#ref-21\">[21]<\/a><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">The National Cancer Institute, as cited by CNBC, says up to 20% of cancer patients receive platinum-based chemotherapy. FDA considered temporary imports from manufacturers not approved for the US market. <a href=\"#ref-21\">[21]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Why Does Price Appear in the Shortage Story?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">Karen Knudsen of the American Cancer Society said in the CNBC report: &#8216;We need it to be financially viable for manufacturing to be able to produce effective, affordable cancer therapies.&#8217; <a href=\"#ref-21\">[21]<\/a> The statement links to the next section. Low prices reduce the return on any new supplier program.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>What Happens to Price and Margin After Generic Entry?<\/strong><\/h2>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>FDA Price Ratios by Number of Generic Producers<\/strong><\/h3>\n\n\n\n<blockquote class=\"wp-block-quote is-layout-flow wp-block-quote-is-layout-flow\">\n<p class=\"wp-block-paragraph\">&#8216;The median price of generics relative to brands using AMP is 40% for the drugs in our sample, while the median price ratio using invoice prices is 49%.&#8217; (Conrad &amp; Lutter, FDA, 2019) <a href=\"#ref-7\">[7]<\/a><\/p>\n<\/blockquote>\n\n\n\n<p class=\"wp-block-paragraph\">The FDA report covers products with first generic entry from January 2015 to December 2017. The brand baseline is the average brand price in the three months before generic entry. Prices are in January 2018 dollars. <a href=\"#ref-7\">[7]<\/a><\/p>\n\n\n\n<figure class=\"wp-block-table\"><table class=\"has-fixed-layout\"><thead><tr><th>Generic producers<\/th><th>Median ratio, AMP<\/th><th>Median ratio, invoice<\/th><th>Change in invoice ratio from prior row (analysis)<\/th><\/tr><\/thead><tbody><tr><td>1<\/td><td>0.614<\/td><td>0.696<\/td><td>Not applicable<\/td><\/tr><tr><td>2<\/td><td>0.465<\/td><td>0.562<\/td><td>-19%<\/td><\/tr><tr><td>3<\/td><td>0.322<\/td><td>0.447<\/td><td>-20%<\/td><\/tr><tr><td>4<\/td><td>0.212<\/td><td>0.268<\/td><td>-40%<\/td><\/tr><tr><td>5<\/td><td>0.144<\/td><td>0.152<\/td><td>-43%<\/td><\/tr><tr><td>6<\/td><td>0.061<\/td><td>0.099<\/td><td>-35%<\/td><\/tr><tr><td>7<\/td><td>0.040<\/td><td>0.059<\/td><td>-40%<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<p class=\"wp-block-paragraph\">Source for the first three columns: <a href=\"#ref-7\">[7]<\/a>. AMP means average manufacturer price reported to CMS. Invoice means invoice-based wholesale price from the IQVIA National Sales Perspective database. <a href=\"#ref-7\">[7]<\/a><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">The largest single step in the invoice series is from four to five producers, at 43% (analysis). The medians come from different drugs at each producer count. They are not a time series for one drug. The table shows the shape of price erosion. It does not predict the path of one product.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>IQVIA Data on Year-One and Year-Two Price Declines<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">The IMS Institute (now IQVIA Institute) studied 428 products with generic entry from 2002 to 2014. Prices for all medicines fell 51% in the first year and 57% in the second year. Prices for oral medicines fell 66% in the first year and 74% in the second year. Within five years, oral prices were 80% below the brand price before expiry. <a href=\"#ref-8\">[8]<\/a><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">The same report says that oral generics that entered in 2011 to 2013 were 74% lower within 8 months. The 2002 to 2004 group was 36% lower in the same window. <a href=\"#ref-8\">[8]<\/a> Price erosion became faster over time.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Does Volume Move Faster Than Price?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">A 2013 Brookings study looked at six molecules that lost exclusivity between June 2009 and May 2013. Volume shifts away from brands outpaced price cuts in the first six months. Brands kept raising prices after generic entry. <a href=\"#ref-22\">[22]<\/a> A generic entrant that is not ready on day one loses a market that moves quickly.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Why Price Erosion Weakens Your Position With a Supplier<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">This section is analysis. A supplier or contract manufacturer that receives a qualification request weighs its cost against the return. After LOE, the unit price falls and the volume forecast is lower. The FDA names a lack of incentives to make less profitable drugs as the first root cause of drug shortages. <a href=\"#ref-23\">[23]<\/a><\/p>\n\n\n\n<h4 class=\"wp-block-heading\"><strong>Overlay: Where the Model Lands on the Price Curve<\/strong><\/h4>\n\n\n\n<p class=\"wp-block-paragraph\">A start at LOE puts FDA action in month 14 or month 19 of the model. Both months fall in the second year of generic competition. The slow case gives month 28, in the third year. In IQVIA data, oral prices were already 74% below the pre-expiry brand price in the second year. <a href=\"#ref-8\">[8]<\/a> The year-three figure is not in the IQVIA data we reviewed.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>Why Do Single-Source Medicines Run Short?<\/strong><\/h2>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>FDA&#8217;s Three Root Causes of Drug Shortages<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">FDA&#8217;s 2019 report names three root causes. Manufacturers lack incentives to make less profitable drugs. The market does not reward manufacturers with mature quality systems. Logistical and regulatory challenges make recovery from a disruption hard. <a href=\"#ref-23\">[23]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>How Many Shortages Come From Quality Problems?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">A Greenleaf Health column reports that quality problems caused 62% of the drug shortages from 2013 to 2017 in the FDA analysis. The task force studied 163 drugs. <a href=\"#ref-24\">[24]<\/a> The FDA web page we reviewed does not show this percentage. We cite the column for it and we cite FDA for the root causes.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>What Do the 2026 Shortage Counts Show?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">ASHP and the University of Utah counted 227 active shortages in the second quarter of 2026. That was the third quarterly increase in a row. <a href=\"#ref-9\">[9]<\/a> Becker&#8217;s Hospital Review reported that 48% of new drug shortages in 2026 involve medicines made by a single manufacturer. The article cites ASHP for other counts. It does not name the source of the 48% figure. <a href=\"#ref-25\">[25]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>How Concentrated Are Starting Materials?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">Pharma Manufacturing reported in April 2026 on a USP analysis. USP found that 41% of the key starting materials used to make medicines for the US come only from China. <a href=\"#ref-26\">[26]<\/a><\/p>\n\n\n\n<h4 class=\"wp-block-heading\"><strong>A Second API Supplier With the Same Starting Material Is Not a Second Source<\/strong><\/h4>\n\n\n\n<p class=\"wp-block-paragraph\">This point is analysis. Two API manufacturers that buy the same key starting material from the same plant share one failure point. A second-source program should include a check of the key starting material source for each candidate.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>What Do 180-Day Exclusivity Rules Mean for Generic Launch Readiness?<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">A first applicant can lose 180-day exclusivity if it does not obtain tentative approval within 30 months of filing. <a href=\"#ref-27\">[27]<\/a> Supply readiness is part of that clock.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Which Forfeiture Clocks Apply?<\/strong><\/h3>\n\n\n\n<figure class=\"wp-block-table\"><table class=\"has-fixed-layout\"><thead><tr><th>Forfeiture event<\/th><th>Deadline<\/th><th>Source<\/th><\/tr><\/thead><tbody><tr><td>Failure to market<\/td><td>The later of two dates: the earlier of 75 days after approval is effective or 30 months after submission, and 75 days after certain court or settlement events<\/td><td><a href=\"#ref-27\">[27]<\/a><\/td><\/tr><tr><td>Failure to obtain tentative approval<\/td><td>30 months after the application is filed; a citizen petition extends the period<\/td><td><a href=\"#ref-27\">[27]<\/a><\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>What Did the D.C. Circuit Decide in Norwich v. Kennedy?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">In August 2026, the D.C. Circuit decided Norwich v. Kennedy (No. 25-5137) on rifaximin. Actavis was the first applicant. The court held that FDA used the wrong causation standard for forfeiture by failure to obtain tentative approval. The statute requires but-for causation. The court sent the question back to FDA. The court also called the exclusivity &#8216;a single, indivisible exclusivity period.&#8217; <a href=\"#ref-28\">[28]<\/a><\/p>\n\n\n\n<h4 class=\"wp-block-heading\"><strong>What This Means for Supply Readiness<\/strong><\/h4>\n\n\n\n<p class=\"wp-block-paragraph\">An applicant that lists an alternate API source in the pending ANDA avoids a later supplement. The FDA presentation says an alternate API source applies to pending ANDAs and to ANDA supplements. <a href=\"#ref-5\">[5]<\/a> A first applicant that adds the second source during the 30-month window uses time that the exclusivity rules already give it.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>What This Means for Brand Manufacturers, Generic Applicants, CDMOs and Buyers<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">This section is analysis. It applies the documented facts above to four groups.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>What This Means for Brand Manufacturers<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">A brand company that plans an authorized generic, or that wants to keep supplying a smaller market, needs approved capacity before LOE. A supplement filed after LOE reaches FDA action in the second or third year of generic competition in our model. File the second-source supplement while the brand price still supports the cost. Check the reporting category under 21 CFR 314.70 and the 2004 guidance, because the FDA presentation we cite does not cover NDAs. <a href=\"#ref-5\">[5]<\/a><a href=\"#ref-11\">[11]<\/a><a href=\"#ref-13\">[13]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>What This Means for Generic Applicants and First Filers<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">A generic applicant that wants a stable launch should plan two API sources before it files, or while the ANDA is pending. FDA states that an alternate API source applies to pending ANDAs. <a href=\"#ref-5\">[5]<\/a> The 30-month tentative approval clock for first applicants adds a deadline to that plan. <a href=\"#ref-27\">[27]<\/a> The MSN example shows that approval can come a year before the patent date. <a href=\"#ref-16\">[16]<\/a><a href=\"#ref-1\">[1]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>What This Means for CDMOs and API Suppliers<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">A supplier that holds an inspected site and a documented process has an advantage when a customer asks for a second source. The FDA CBE-30 exception applies when the API site has satisfactory CGMP status and the source is already approved for the same applicant. <a href=\"#ref-5\">[5]<\/a> Suppliers that disclose their key starting material sources help customers avoid a hidden shared failure point. <a href=\"#ref-26\">[26]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>What This Means for Hospital and Payer Procurement Teams<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">Ask each supplier how many FDA-approved API sources support each product. Forty-eight percent of new 2026 shortages involve single-manufacturer medicines, according to Becker&#8217;s. <a href=\"#ref-25\">[25]<\/a> A contract with a second approved source costs less than an emergency import. FDA considered imports in the 2023 platinum drug shortage. <a href=\"#ref-21\">[21]<\/a><\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>A T-Minus Checklist for Second-Source Readiness<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">The table counts back from the earliest credible LOE date. The start points come from our lead-time model. They are not FDA requirements.<\/p>\n\n\n\n<figure class=\"wp-block-table\"><table class=\"has-fixed-layout\"><thead><tr><th>Months before LOE<\/th><th>Action<\/th><th>Basis<\/th><\/tr><\/thead><tbody><tr><td>34 or more<\/td><td>Confirm the earliest credible LOE date from the Orange Book, USPTO data, court records and settlements. Start supplier selection if inspection and a second review cycle are possible.<\/td><td>Model, slow case plus one cycle<\/td><\/tr><tr><td>28<\/td><td>Latest start for the slow case. Check the key starting material source of each candidate.<\/td><td>Model; <a href=\"#ref-26\">[26]<\/a><\/td><\/tr><tr><td>19<\/td><td>Latest start for the standard case.<\/td><td>Model<\/td><\/tr><tr><td>14<\/td><td>Latest start for the fast case. Request priority review if the criteria apply.<\/td><td>Model; <a href=\"#ref-6\">[6]<\/a><\/td><\/tr><tr><td>At least 2 before the PAS<\/td><td>Send the complete and accurate PFC, at least 60 days before the supplement.<\/td><td><a href=\"#ref-6\">[6]<\/a><\/td><\/tr><tr><td>0<\/td><td>Approved second source in place. Distribution begins after FDA approval.<\/td><td><a href=\"#ref-11\">[11]<\/a><\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>Which Regulatory Tools Support Second-Source Qualification?<\/strong><\/h2>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Pre-Submission Facility Correspondence<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">A complete PFC sent at least 60 days before a priority PAS moves the inspection goal from 10 months to 8 months. <a href=\"#ref-6\">[6]<\/a> The tool saves two months in the case that needs an inspection. It costs the applicant a plan that is ready 60 days before the filing.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>DMF Review Requests Before a Submission<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">The FDA fiscal year 2025 report lists 16 requests for review of a drug master file before an ANDA or PAS submission. FDA granted 15 and completed 12. It also reviewed 55 off-cycle DMF amendments. <a href=\"#ref-14\">[14]<\/a> The share granted is 94% (analysis: 15 \/ 16). The report does not say how many DMF holders could have used the option.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Section 506C Notices and the Alternative Source Question<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">Section 506C of the FD&amp;C Act requires certain applicants and manufacturers to notify FDA of a permanent discontinuance, or of an interruption likely to cause a meaningful disruption. The duty covers finished products and API. A notice must include the API source and known alternative sources when the API is a reason for, or a risk factor in, the disruption. <a href=\"#ref-29\">[29]<\/a> A company with no qualified alternative has nothing to list in that field (analysis).<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>Methodology and Limitations<\/strong><\/h2>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>What Data We Analyzed<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">We reviewed FDA documents, a federal regulation, SEC filings, company releases, an IQVIA Institute report and news reports. We accessed all sources on October 25, 2026. We chose sources by their link to second-source qualification, generic price erosion, shortages, and the four cases. We did not count Orange Book patents, so this article contains no database count.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>How We Calculated the Figures<\/strong><\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Entresto interval: July 22, 2025 minus July 15, 2025 equals 7 days.<\/li>\n\n\n\n<li>MSN readiness: July 2024 to July 22, 2025 is about 12 months. The source gives only the month of approval.<\/li>\n\n\n\n<li>Entresto sequential change: (1,253 &#8211; 1,877) \/ 1,877 equals -33.2%. Q4 share of year: 1,253 \/ 7,748 equals 16.2%.<\/li>\n\n\n\n<li>Revlimid: (425 &#8211; 838) \/ 838 equals -49.3%. (773 &#8211; 1,774) \/ 1,774 equals -56.4%.<\/li>\n\n\n\n<li>Invoice price ratio: (0.268 &#8211; 0.696) \/ 0.696 equals -61.5%. Each step in the price table is the ratio for the row divided by the ratio for the prior row, minus one.<\/li>\n\n\n\n<li>Valsartan: July 2018 to March 13, 2019 is about eight months.<\/li>\n\n\n\n<li>Lead-time model: the phase durations in the results table are added. Review share is the review phase divided by the total.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Limitations<\/strong><\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Phase A and the batch time in Phase B are our assumptions. FDA publishes no goal for them.<\/li>\n\n\n\n<li>GDUFA goals measure the time to FDA action. An action can be a complete response letter.<\/li>\n\n\n\n<li>The FDA supplier presentation covers ANDAs. NDA classification needs separate confirmation.<\/li>\n\n\n\n<li>The FDA price medians come from different drugs and from entries in 2015 to 2017.<\/li>\n\n\n\n<li>The 62% quality figure comes from a Greenleaf Health column. The 48% single-manufacturer figure comes from a news article that does not name its source. The 41% key starting material figure comes from a news report on a USP analysis.<\/li>\n\n\n\n<li>I-MAK is an advocacy organization. We did not check its Revlimid dates against settlement documents.<\/li>\n\n\n\n<li>Revlimid revenue is global. It is not a US figure.<\/li>\n\n\n\n<li>We do not know any company&#8217;s actual supplier arrangements for Entresto.<\/li>\n<\/ul>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>Key Takeaways<\/strong><\/h2>\n\n\n\n<ul class=\"wp-block-list\">\n<li>FDA says an alternate API source for an ANDA belongs in a prior approval supplement. <a href=\"#ref-5\">[5]<\/a><\/li>\n\n\n\n<li>The GDUFA III goals are 6 months for a standard PAS and 10 months when an inspection is required. <a href=\"#ref-6\">[6]<\/a><\/li>\n\n\n\n<li>FDA asks for at least 3 months of long-term and 3 months of accelerated drug product stability data. <a href=\"#ref-5\">[5]<\/a><\/li>\n\n\n\n<li>Our lead-time model gives 14, 19 and 28 months, and 20, 25 and 34 months with one more review cycle (analysis).<\/li>\n\n\n\n<li>The first generic Entresto launched seven days after patent expiry. Q4 2025 net sales fell 43% in US dollars. <a href=\"#ref-1\">[1]<\/a><a href=\"#ref-2\">[2]<\/a><a href=\"#ref-3\">[3]<\/a><\/li>\n\n\n\n<li>The median invoice-based generic price ratio is 0.268 with four producers, against 0.696 with one. <a href=\"#ref-7\">[7]<\/a><\/li>\n\n\n\n<li>In 2026, ASHP counted 227 active shortages in the second quarter. Becker&#8217;s reported that 48% of new shortages involve a single manufacturer. <a href=\"#ref-9\">[9]<\/a><a href=\"#ref-25\">[25]<\/a><\/li>\n\n\n\n<li>Plan to the earliest credible LOE date. Check the starting material source of each second-source candidate (analysis).<\/li>\n<\/ul>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>FAQ: Second-Source Supplier Qualification and the Patent Cliff<\/strong><\/h2>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>How long does FDA take to review a PAS for a new API source?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">The GDUFA III goal is 6 months for a standard PAS without an inspection and 10 months with one. The priority goals are 4 and 8 months. <a href=\"#ref-6\">[6]<\/a> The goal measures the time to FDA action, not the time to approval.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Can a company add a second API supplier with a CBE-30?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">Only in one case that FDA lists. The same applicant must already have the source approved by PAS in another ANDA. The API sites must have satisfactory CGMP status. <a href=\"#ref-5\">[5]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>How much stability data does FDA expect for an alternate API source?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">FDA lists a minimum of 3 months of long-term and 3 months of accelerated drug product stability data. It also asks for at least one pilot-scale or commercial-scale batch. <a href=\"#ref-5\">[5]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Does an NDA holder follow the same process as an ANDA holder?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">The FDA presentation on alternate API sources does not address NDAs. <a href=\"#ref-5\">[5]<\/a> An NDA holder classifies the change under 21 CFR 314.70 and the 2004 FDA guidance. <a href=\"#ref-11\">[11]<\/a><a href=\"#ref-13\">[13]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>What happens if a first applicant does not get tentative approval in time?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">The applicant can forfeit 180-day exclusivity if it does not obtain tentative approval within 30 months of filing. <a href=\"#ref-27\">[27]<\/a> In Norwich v. Kennedy, the D.C. Circuit held that FDA must use but-for causation in this analysis. <a href=\"#ref-28\">[28]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Does FDA need to know when API supply is at risk?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">Section 506C covers API discontinuance and interruption. The notice must name the API source and known alternative sources where the API is a reason or risk factor. <a href=\"#ref-29\">[29]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>How fast do generic prices fall after entry?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">In IQVIA data on products with generic entry from 2002 to 2014, oral medicine prices fell 66% in year one and 74% in year two. <a href=\"#ref-8\">[8]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>How many generic producers does it take to reach a 90% price discount?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">In FDA data, the median invoice-based ratio is 0.099 with six producers. That is about 90% below the brand baseline (analysis). The median AMP ratio is 0.061 with six producers. <a href=\"#ref-7\">[7]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Why do single-manufacturer medicines run short more often?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">FDA names weak incentives, weak market rewards for quality, and slow recovery after a disruption as root causes. <a href=\"#ref-23\">[23]<\/a> Becker&#8217;s reported that 48% of new 2026 shortages involve a single manufacturer. <a href=\"#ref-25\">[25]<\/a> A single-source product has no approved fallback.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Where can I find the dates that start the second-source clock?<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">Use the FDA Orange Book, USPTO data, court records and company filings. DrugPatentWatch lists patent expiry opportunities and says it draws on the USPTO, the Orange Book, ANDA filings and litigation records. <a href=\"#ref-4\">[4]<\/a> Plan to the earliest credible date, because litigation and settlements can move it. <a href=\"#ref-2\">[2]<\/a><\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>References<\/strong><\/h2>\n\n\n\n<ol class=\"wp-block-list\">\n<li>Optum Rx. (2025, July 30). <em>New generic: Entresto (sacubitril\/valsartan)<\/em> [Provider notice]. https:\/\/business.optum.com\/en\/support\/professionalrx-resources\/newgeneric-entresto-073025.html<\/li>\n\n\n\n<li>Novartis AG. (2023, July 7). <em>Novartis will appeal US court decision on Entresto combination patent<\/em> [Media release]. https:\/\/www.novartis.com\/news\/media-releases\/novartis-will-appeal-us-court-appeals-uphold-validity-entresto-combination-patent-maintains-2023-guidance-and-mid-term-outlook<\/li>\n\n\n\n<li>Novartis AG. (2026, February 4). <em>Form 6-K: Fourth quarter and full year 2025 results<\/em>. U.S. Securities and Exchange Commission. https:\/\/www.sec.gov\/Archives\/edgar\/data\/1114448\/000111444826000007\/a260204-99_2.htm<\/li>\n\n\n\n<li>DrugPatentWatch. (n.d.). <em>Home<\/em>. https:\/\/www.drugpatentwatch.com\/<\/li>\n\n\n\n<li>Paul, R., &amp; Jiang, B. (2023, April). <em>Change in API supplier: Drug product quality tips<\/em> [Presentation]. SBIA Generic Drug Forum, U.S. Food and Drug Administration. https:\/\/fda.gov\/media\/168954\/download<\/li>\n\n\n\n<li>U.S. Food and Drug Administration. (n.d.). <em>GDUFA reauthorization performance goals and program enhancements, fiscal years 2023-2027<\/em>. https:\/\/www.fda.gov\/media\/153631\/download<\/li>\n\n\n\n<li>Conrad, R., &amp; Lutter, R. (2019, December). <em>Generic competition and drug prices: New evidence linking greater generic competition and lower generic drug prices<\/em>. U.S. Food and Drug Administration. https:\/\/fda.gov\/media\/133509\/download<\/li>\n\n\n\n<li>IMS Institute for Healthcare Informatics. (2016, January). <em>Price declines after branded medicines lose exclusivity in the U.S.<\/em> IQVIA. https:\/\/www.iqvia.com\/-\/media\/iqvia\/pdfs\/institute-reports\/price-declines-after-branded-medicines-lose-exclusivity-in-the-us.pdf<\/li>\n\n\n\n<li><em>AJMC<\/em>. (2026, July 20). Active US drug shortages rise for third straight quarter. https:\/\/www.ajmc.com\/view\/active-us-drug-shortages-rise-for-third-straight-quarter<\/li>\n\n\n\n<li><em>CBS News<\/em>. (2019, March 13). After multiple recalls, FDA approves new generic for valsartan. https:\/\/www.cbsnews.com\/amp\/news\/valsartan-generic-approved-after-drug-recalls-fda-approves-new-generic-for-high-blood-pressure<\/li>\n\n\n\n<li>U.S. Government Publishing Office. (2024). <em>21 C.F.R. 314.70: Supplements and other changes to an approved NDA<\/em>. https:\/\/www.govinfo.gov\/content\/pkg\/CFR-2024-title21-vol5\/pdf\/CFR-2024-title21-vol5-sec314-70.pdf<\/li>\n\n\n\n<li>Patel, H. B. (2015, September 30). <em>An overview of post-marketing activities for NDAs<\/em> [Presentation]. Redl Conference, U.S. Food and Drug Administration. https:\/\/fda.gov\/media\/94067\/download<\/li>\n\n\n\n<li>U.S. Food and Drug Administration. (2004, April). <em>Guidance for industry: Changes to an approved NDA or ANDA<\/em> (Revision 1). https:\/\/fda.gov\/media\/71846\/download<\/li>\n\n\n\n<li>U.S. Food and Drug Administration. (n.d.). <em>Generic drugs program fiscal year 2025 activities report<\/em>. https:\/\/www.fda.gov\/industry\/generic-drug-user-fee-amendments\/generic-drugs-program-fiscal-year-2025-activities-report<\/li>\n\n\n\n<li>IntuitionLabs. (n.d.). <em>Drug patent expirations 2027-2030 calendar<\/em>. https:\/\/intuitionlabs.ai\/articles\/drug-patent-expirations-2027-2030-calendar<\/li>\n\n\n\n<li><em>Nasdaq<\/em>. (2024, August 15). Novartis&#8217; (NVS) motion to block Entresto generic denied: What&#8217;s next? https:\/\/www.nasdaq.com\/articles\/novartis-nvs-motion-block-entresto-generic-denied-whats-next<\/li>\n\n\n\n<li>Novartis AG. (2025, October 28). <em>Form 6-K: Third quarter 2025 results<\/em>. U.S. Securities and Exchange Commission. https:\/\/www.sec.gov\/Archives\/edgar\/data\/1114448\/000111444825000003\/a251028-99_2.htm<\/li>\n\n\n\n<li>I-MAK. (2025, April 4). <em>How Celgene and Bristol Myers Squibb used volume restrictions to delay Revlimid competition<\/em>. https:\/\/www.i-mak.org\/2025\/04\/04\/how-celgene-and-bristol-myers-squibb-used-volume-restrictions-to-delay-revlimid-competition\/<\/li>\n\n\n\n<li>Bristol-Myers Squibb Company. (2026). <em>Form 10-Q for the quarterly period ended June 30, 2026<\/em>. U.S. Securities and Exchange Commission. https:\/\/www.sec.gov\/Archives\/edgar\/data\/0000014272\/000001427226000020\/bmy-20260630.htm<\/li>\n\n\n\n<li><em>BioPharma Dive<\/em>. (2018, August 31). FDA widens valsartan probe, recalls. https:\/\/www.biopharmadive.com\/news\/fda-widens-valsartan-probe-recalls\/531405\/<\/li>\n\n\n\n<li><em>CNBC<\/em>. (2023, June 1). FDA considers temporary cancer drug imports from unapproved companies to ease U.S. shortage. https:\/\/www.cnbc.com\/2023\/06\/01\/cancer-drug-shortage-fda-mulls-overseas-chemotherapy-imports.html<\/li>\n\n\n\n<li>Aitken, M. L., Berndt, E. R., Bosworth, B. P., Cockburn, I. M., Frank, R. G., Kleinrock, M., &amp; Shapiro, B. T. (2013, October 1). <em>The regulation of prescription drug competition and market responses: Patterns in prices and sales following loss of exclusivity<\/em>. Brookings Institution. https:\/\/www.brookings.edu\/articles\/the-regulation-of-prescription-drug-competition-and-market-responses-patterns-in-prices-and-sales-following-loss-of-exclusivity\/<\/li>\n\n\n\n<li>U.S. Food and Drug Administration. (2019, October). <em>Report: Drug shortages: Root causes and potential solutions<\/em>. https:\/\/www.fda.gov\/drugs\/drug-shortages\/report-drug-shortages-root-causes-and-potential-solutions<\/li>\n\n\n\n<li>Giaquinto, &amp; Schnedar. (2019, December 27). An analysis of the FDA&#8217;s drug shortages root cause report [Guest column]. <em>Outsourced Pharma<\/em>. https:\/\/www.outsourcedpharma.com\/doc\/an-analysis-of-the-fda-s-drug-shortages-root-cause-report-0001<\/li>\n\n\n\n<li><em>Becker&#8217;s Hospital Review<\/em>. (2026, July 16). 1 in 2 new drug shortages tied to single manufacturers: 5 shortage updates to know. https:\/\/www.beckershospitalreview.com\/pharmacy\/1-in-2-new-drug-shortages-tied-single-manufacturers-5-shortage-updates-to-know\/<\/li>\n\n\n\n<li><em>Pharma Manufacturing<\/em>. (2026, April 14). US drug supply at risk from single-country KSM sources: Report. https:\/\/www.pharmamanufacturing.com\/quality-risk\/supply-chain\/article\/55370724\/us-drug-supply-at-risk-from-single-country-ksm-sources-report<\/li>\n\n\n\n<li>Berkeley Law. (2024). <em>180 day generic drug exclusivity: Forfeiture<\/em>. https:\/\/law.berkeley.edu\/wp-content\/uploads\/2024\/05\/180-Day-Generic-Drug-Exclusivity-%E2%80%93-Forfeiture.pdf<\/li>\n\n\n\n<li><em>FDA Law Blog<\/em>. (2026, August). A costly 180: The D.C. Circuit flips FDA&#8217;s forfeiture playbook. https:\/\/www.thefdalawblog.com\/2026\/08\/a-costly-180-the-d-c-circuit-flips-fdas-forfeiture-playbook\/<\/li>\n\n\n\n<li>U.S. Food and Drug Administration. (2023, April 6). Notice, Doc. 2023-07238, 88 Fed. Reg. (66) [Notification of discontinuance or interruption in manufacturing]. https:\/\/www.govinfo.gov\/content\/pkg\/FR-2023-04-06\/html\/2023-07238.htm<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"<p>The first generic Entresto reached US pharmacies on July 22, 2025. [1] Novartis had said in 2023 that the combination [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":40014,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_lmt_disableupdate":"","_lmt_disable":"","site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"default","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","ast-disable-related-posts":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"footnotes":""},"categories":[10],"tags":[],"class_list":["post-40013","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-insights"],"modified_by":"DrugPatentWatch","_links":{"self":[{"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/posts\/40013","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/comments?post=40013"}],"version-history":[{"count":1,"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/posts\/40013\/revisions"}],"predecessor-version":[{"id":40015,"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/posts\/40013\/revisions\/40015"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/media\/40014"}],"wp:attachment":[{"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/media?parent=40013"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/categories?post=40013"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/tags?post=40013"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}