Post-approval indications and clinical trials for cardiovascular drugs: some implications of the US Inflation Reduction Act.

OBJECTIVE: To describe the historical baseline landscape of cardiovascular drug post-approval activity, including the number and timing of post-approval clinical trials and approved indications. The US Inflation Reduction Act of 2022 (IRA) Drug Price Negotiation Program (DPNP) and its Maximum Fair Prices (MFPs) will affect incentives for investment in post-approval activity such as clinical trials for new indications. While three of the first ten drugs selected for the DPNP and MFP-setting are cardiovascular or antithrombotic drugs, limited attention has been paid to potential cardiovascular drug impacts, and to post-approval innovation. METHODS: For the 65 drugs originally approved by the FDA from 1995 through 2021 for a cardiovascular or antithrombotic indication (60 small molecules and 5 biologics), we develop a novel dataset of industry-sponsored, post-approval clinical trials and FDA-approved label changes for new indications. We analyze their number and timing relative to DPNP drug selection and MFP implementation dates, by drug approval-year cohort. RESULTS: We find 49% of indications were awarded and 76% of industry-funded clinical trials were completed post-approval, reaching 98% of trials for drugs in the earliest 1995-99 cohort. For the 60 small molecules, 76% of post-approval trials ended five years or more after original drug approval, 65% ended seven or more years after original drug approval (i.e. after potential DPNP selection), and 53% nine or more years after original drug approval (i.e. after potential MFP implementation). CONCLUSIONS: Post-approval FDA indication approvals and clinical trial starts and primary completion dates often occurred after or near new DPNP selection and MFP implementation dates. This has economic consequences for future investment incentives. Post-approval trials for small molecules, longer-duration trials, and larger-enrollment trials, and post-approval indications focused on limited patient populations and older patients could face particular economic challenges.

Continuing trends in U.S. brand-name and generic drug competition.

OBJECTIVE: To provide updated evidence in a series of analyses of U.S. trends over the past two decades in key financial metrics for branded drugs: market exclusivity periods (MEPs, the time between launch and first generic entry) for new molecular entities (NMEs); the probability, timing and number of patent challenges under Paragraph IV of the Hatch-Waxman Act; and the intensity of generic penetration. METHODS: As previously, we used IQVIA National Sales Perspectives U.S. data to calculate MEPs for the 356 NMEs experiencing initial generic entry from 1995 through 2019, the number of generic competitors for twelve months afterward (by prior sales level), and generic shares. We calculated the probability, timing and number of Paragraph IV challengers using Abbreviated New Drug Application (ANDA) approval letters, the FDA website, public information searches, and ParagraphFour.com. RESULTS: For NMEs experiencing initial generic entry in 2017-19, the MEP was 13.0 years for drugs with sales greater than $250 million in 2008 dollars the year before generic entry (NMEs>$250 million), 14.1 years overall. One year later, brands' average unit share was 18% for NMEs>$250 million, 23% overall. Ninety-three percent of NMEs>$250 million experiencing initial generic entry faced at least one Paragraph IV challenge (2019, three-year rolling average), an average of 6.0 years after brand launch (81% and 6.3 years for all NMEs). NMEs faced an average of 6.8 and 8.9 Paragraph IV challengers per NME, for all and NMEs>$250 million, respectively (2017-19 figures). LIMITATIONS: All analyses were restricted to NMEs experiencing generic entry. CONCLUSION: The average 2017-19 MEP of 13.0 years for NMEs>$250 million has changed relatively little over the past decade and remains lower than for all NMEs (14.1 years). Paragraph IV challenges are more frequent and occur earlier for NMEs>$250 million. Generic share erosion remains high for both NME types.

Financing Drug Innovation in the US: Current Framework and Emerging Challenges.

The current US drug innovation financing framework rests on the notion that a defined period of marketing exclusivity combined with the expectation of reimbursement for clinically valuable, cost-effective therapies, followed by vigorous price competition from generic drugs and biosimilars ensures a sufficient return on investment (ROI) to incent private sector risk-based investment and research and development activities while providing access for new treatments to patients. While periodically, alternatives such as government prizes, direct purchases or development, and limits on certain incentives have been proposed, the basic approach has remained intact since the 1980s, with incremental provisions addressing specific gaps and priorities, and adding provisions for biosimilar entry. This paper reviews the main elements of the current US system to financing drug innovation and its approach to balancing multiple objectives. In addition, the system for financing drug innovation must be effective over a wide range of potential scientific approaches and economic conditions. It should be predictable for investors and payers making long-term development and coverage decisions, while also encompassing unanticipated new treatment modalities and scientific progress. An important emerging challenge is posed by clinically transformative, high-investment, single-administration therapies, such as gene therapy. Continued experimentation and the input of a range of stakeholders are needed to ensure next-generation therapeutic advances continue to be developed and made available to patients.

Federal government-interest patent disclosures for recent top-selling drugs.

Objective: To provide updated evidence on government-interest patent disclosures in US patents for top-selling small-molecule drugs.Methods: IQVIA National Sales Perspectives data identified 300 top-selling drugs, defined by peak 2013-2017 US sales. For the 197 approved through New Drug Applications (NDAs), data were collected from a recently-released dataset of all patents listed in 1985-2016 Annual Editions of the FDA Orange Book. Data on patent assignees and Government Interest Statements (if any) were collected from the US Patent and Trademark Office online database. The percentage of drugs with at least one government-interest patent disclosure was calculated, as was the percentage of patents with a disclosure, by type (drug product, drug substance, or method of use). Government-interest patent disclosures were defined as those for which: the patent application contained a Government Interest Statement; and/or any of the patent assignees was a US government agency.Results: Few patents for the top-selling drugs had a government-interest patent disclosure, 2.6% on average. By patent type, figures ranged between 1.6% (for patents with drug product claims) and 3.6% (for patents with drug substance claims). Accounting for multiple patents per drug, 8.6% of top-selling drugs analyzed had at least one patent with a Government Interest Statement; 1.5% had at least one with a US government agency assignee; and 10.2% met either criterion (none met both).Limitations: Analyses were limited to top-selling NDA-approved drugs (generally excluding biologics) and Orange Book-listed patents. Patents with government-interest patent disclosures could also have relied on non-government funding. Patents were not characterized by relative economic investments, importance in the discovery and development process, or contribution to clinical value.Conclusion: Results were generally comparable to a prior analysis that found that 9.0% of new drugs approved between 1988 and 2005 had either a Government Interest Statement disclosure or a government agency first-listed patent assignee.

Insurance switching and mismatch between the costs and benefits of new technologies.

OBJECTIVES: Many therapies have immediate costs but delayed benefits. Recent and anticipated transformative therapies may exacerbate these challenges. This study explored whether disconnects between short-term budget impacts and long-term costs and benefits, and among impacts on initial payers, downstream payers, and society, are expected for a range of such therapies and whether they are likely consistent or variable, with implications for potential policy responses. STUDY DESIGN: Modeling. METHODS: We modeled the impacts of 5 hypothetical therapies affecting different patient types: curative gene therapy for a childhood disorder, highly effective hepatitis C virus therapy, disease-modifying Alzheimer disease therapy, and cardiovascular disease therapy for both rare genetic and higher-risk prior cardiovascular event populations. We constructed disease-specific models, modifying best-available Markov analysis estimates for standard-of-care state transition rates, utilities, and costs. We disaggregated total healthcare impacts into impacts on initial versus downstream payers, dividing payers into 3 types: commercial insurers, Medicaid, and Medicare. RESULTS: Although we found gaps between the impacts on initial and downstream payers in all examples, some substantial, the magnitude and reasons vary. CONCLUSIONS: As scientific advances generate transformative therapies with substantial structural disconnects between "who pays" and "who benefits," creative approaches may be needed by manufacturers, payers, and others to ensure appropriate access to cost-effective therapies, adequate economic incentives for future development, and sustainable payer economics. Mechanisms may amortize high up-front costs over time, provide for transfers among payers, or a combination. Our research suggests that approaches should be tailored to specific disease and therapy characteristics to be effective.

Updated trends in US brand-name and generic drug competition.

OBJECTIVE: To provide updated evidence on US trends in: market exclusivity periods (MEPs, time between brand-name drug launch and first generic competitors) for new molecular entities (NMEs); likelihood, timing and number of Hatch-Waxman Act Paragraph IV patent challenges; and generic drug penetration. METHODS: This study used IMS Health National Sales Perspectives(TM) US data to calculate MEPs for the 288 NMEs experiencing initial generic entry between January 1995 and December 2014, the number of generic competitors for 12 months afterward (by level of annual sales prior to generic entry), and generic penetration rates. The likelihood, timing and number of Paragraph IV challengers were calculated using data from Abbreviated New Drug Approval (ANDA) letters, the FDA website, public information searches, and ParagraphFour.com. RESULTS: For drugs experiencing initial generic entry in 2013-2014, the MEP was 12.5 years for drugs with sales greater than $250 million (in 2008 dollars) in the year prior to generic entry ($250 million + NMEs), 13.6 years overall. After generic entry, brands rapidly lost sales, with their average unit share being 7% at 1 year for $250 million + NMEs, 12% overall. Ninety-four percent of $250 million + NMEs experiencing initial generic entry in 2013-2014 had faced at least one Paragraph IV challenge, an average of 5.2 years after brand launch (76% and 5.9 years for all NMEs). NMEs faced an average of 5.1 and 6.2 Paragraph IV challenges per NME, for all and $250 million + NMEs, respectively. LIMITATIONS: Analyses, including Paragraph IV calculations, were restricted to NMEs where generic entry had occurred. CONCLUSION: The average 2013-2014 MEP of 12.5 years for $250 million + NMEs, 13.6 overall remains consistent with prior research. MEPs are lower, and Paragraph IV challenges are more frequent and occur earlier for $250 million + drugs. Generic share erosion is also greater, and continues to intensify for both NME types.

The importance of patents to innovation: updated cross-industry comparisons with biopharmaceuticals.

Patents have long been considered essential incentives to foster innovation, particularly the development of new prescription drugs, due to the lengthy, costly, and risky nature of the research and development (R&D) process as compared to the lower levels of investment and risk associated with generic drug entry. Compared with other forms of intellectual property protection (such as trade secrets, trademarks, and copyrights) and strategic complementary assets (such as lead time, sales and service, and manufacturing advantages), researchers focused on the US since the 1980s consistently have found patents to be relatively more important to R&D in pharmaceuticals than in other industries. Despite many changes in the market and patent landscape, the most recent data from government surveys and annual surveys of licensing professionals continue to find differential and high importance of patents to biopharmaceutical innovation.

The roles of patents and research and development incentives in biopharmaceutical innovation.

Patents and other forms of intellectual property protection play essential roles in encouraging innovation in biopharmaceuticals. As part of the "21st Century Cures" initiative, Congress is reviewing the policy mechanisms designed to accelerate the discovery, development, and delivery of new treatments. Debate continues about how best to balance patent and intellectual property incentives to encourage innovation, on the one hand, and generic utilization and price competition, on the other hand. We review the current framework for accomplishing these dual objectives and the important role of patents and regulatory exclusivity (together, the patent-based system), given the lengthy, costly, and risky biopharmaceutical research and development process. We summarize existing targeted incentives, such as for orphan drugs and neglected diseases, and we consider the pros and cons of proposed voluntary or mandatory alternatives to the patent-based system, such as prizes and government research and development contracting. We conclude that patents and regulatory exclusivity provisions are likely to remain the core approach to providing incentives for biopharmaceutical research and development. However, prizes and other voluntary supplements could play a useful role in addressing unmet needs and gaps in specific circumstances.

Evolving provider payment models and patient access to innovative medical technology.

UNLABELLED: Abstract Objective: To investigate the evolving use and expected impact of pay-for-performance (P4P) and risk-based provider reimbursement on patient access to innovative medical technology. METHODS: Structured interviews with leading private payers representing over 110 million commercially-insured lives exploring current and planned use of P4P provider payment models, evidence requirements for technology assessment and new technology coverage, and the evolving relationship between the two topics. RESULTS: Respondents reported rapid increases in the use of P4P and risk-sharing programs, with roughly half of commercial lives affected 3 years ago, just under two-thirds today, and an expected three-quarters in 3 years. All reported well-established systems for evaluating new technology coverage. Five of nine reported becoming more selective in the past 3 years in approving new technologies; four anticipated that in the next 3 years there will be a higher evidence requirement for new technology access. Similarly, four expected it will become more difficult for clinically appropriate but costly technologies to gain coverage. All reported planning to rely more on these types of provider payment incentives to control costs, but didn't see them as a substitute for payer technology reviews and coverage limitations; they each have a role to play. LIMITATIONS: Interviews limited to nine leading payers with models in place; self-reported data. CONCLUSION: Likely implications include a more uncertain payment environment for providers, and indirectly for innovative medical technology and future investment, greater reliance on quality and financial metrics, and increased evidence requirements for favorable coverage and utilization decisions. Increasing provider financial risk may challenge the traditional technology adoption paradigm, where payers assumed a 'gatekeeping' role and providers a countervailing patient advocacy role with regard to access to new technology. Increased provider financial risk may result in an additional hurdle to the adoption of new technology, rather than substitution of provider- for payer-based gatekeeping.

Recent trends in brand-name and generic drug competition.

OBJECTIVE: To provide evidence on recent trends in: (1) market exclusivity periods (MEPs, the time between launch of a brand-name drug and its first generic competitor) for new molecular entities (NMEs); (2) the likelihood and timing of patent challenges under Paragraph IV of the Hatch-Waxman Act; and (3) generic drug penetration. METHODS: IMS Health National Sales Perspectives data were used to calculate MEPs for the 257 NMEs experiencing initial generic entry between January 1995 and September 2012 and the number of generic competitors for 12 months afterwards, by level of annual sales prior to generic entry and time period. The likelihood and timing of Paragraph IV challenge were calculated using data from Abbreviated New Drug Approval (ANDA) approval letters, the FDA website, and public information searches to identify drugs experiencing Paragraph IV filings, and the first filing date. RESULTS: For drugs experiencing initial generic entry in 2011-2012, the MEP was 12.6 years for drugs with sales greater than $100 million (in 2008 dollars) in the year prior to generic entry, 12.9 years overall. After generic entry, the brand rapidly lost sales, with average brand unit share of 16% at 1 year; 11% for NMEs with pre-generic entry sales of at least $250 million (in 2008 dollars). Over 80% of NMEs experiencing 2011-2012 initial generic entry had faced at least one Paragraph IV challenge from a generic manufacturer. These challenges were filed relatively early in the brand-name drug life cycle: within 7 years after brand launch, on average. LIMITATIONS: Analyses, including Paragraph IV calculations, were restricted to NMEs where generic entry had occurred. CONCLUSION: Pharmaceutical competition continues to evolve; while the average MEP below 13 years for 2011-2012 remains consistent with prior research, Paragraph IV challenges are increasingly frequent and occur earlier, and generic share erosion has intensified.

Assessing the impact of substandard copy medicines in developing countries: the experience with imatinib copies.

Access to safe, high-quality medicines is an important international healthcare issue. In developing countries, copy medicines may be attractive due to low acquisition price, but their potential risks due to inadequately demonstrated bioequivalence have garnered only limited attention. As a result, policy-makers, physicians and patients may have incomplete information regarding their real-world safety and efficacy. Using chronic myeloid leukemia (CML) treatment as an example, we conducted a literature review of case reports and study publications to assess whether the available literature provides evidence on the real-world safety and efficacy of imatinib copies. While several publications described clinical outcomes with imatinib copy treatment, significant gaps in interpretability and quality exist. We conclude that clear demonstration of bioequivalence is critical for copy drugs, and in the presence of uncertain bioequivalence, greater pharmacovigilance and real-world data benchmarked against originator medications are needed to assess the impact of copy medicines and protect patients in developing countries.

Evolving brand-name and generic drug competition may warrant a revision of the Hatch-Waxman Act.

The evolution of pharmaceutical competition since Congress passed the Hatch-Waxman Act in 1984 raises questions about whether the act's intended balance of incentives for cost savings and continued innovation has been achieved. Generic drug usage and challenges to brand-name drugs' patents have increased markedly, resulting in greatly increased cost savings but also potentially reduced incentives for innovators. Congress should review whether Hatch-Waxman is achieving its intended purpose of balancing incentives for generics and innovation. It also should consider whether the law should be amended so that some of its provisions are brought more in line with recently enacted legislation governing approval of so-called biosimilars, or the corollary for biologics of generic competition for small-molecule drugs.

Commercial importation of prescription drugs in the United States: short-run implications.

The option of legalizing the commercial importation of prescription drugs is of continued policy interest as a way to reduce U.S. drug spending. Using IMS data, we estimate potential savings from commercial drug importation under assumptions about percentage of drugs likely to attract imports; potential supply from foreign countries; and share of savings passed on to payers. Our base case estimate is that $1.7 billion per year, or 0.6 percent of total drug spending, would be saved by payers; sensitivity analyses range from 0.2 to 2.5 percent under plausible assumptions and up to 17.4 percent under unrealistic assumptions about unlimited foreign supply, costless trade, and zero profits for intermediaries. Estimated savings to payers are less than the average price differentials between the United States and foreign countries because proposed legislation exempts certain drugs from importation; foreign markets are small relative to the United States; regulatory and other constraints may limit the volume of exports; trade is costly; and intermediaries will retain some savings. Although savings to U.S. payers/consumers would likely be small and have minimal impact on total U.S. health care spending, costs to other countries could be significant, due to reduced access and possibly higher prices. In the long run, reduced investment in R&D could adversely affect consumers globally.

The value of antihypertensive drugs: a perspective on medical innovation.

Using national survey data and risk equations from the Framingham Heart Study, we quantify the impact of antihypertensive therapy changes on blood pressures and the number and cost of heart attacks, strokes, and deaths. Antihypertensive therapy has had a major impact on health. Without it, 1999-2000 average blood pressures (at age 40+) would have been 10-13 percent higher, and 86,000 excess premature deaths from cardiovascular disease would have occurred in 2001. Treatment has generated a benefit-to-cost ratio of at least 6:1, but much more can be achieved. More effective use of antihypertensive medication would have an impact on mortality akin to eliminating all deaths from medical errors or accidents.

The market for follow-on biologics: how will it evolve?

With spending on biologics rising and patent expiry approaching for several blockbuster biologics, Congress and the Food and Drug Administration are considering creating a clear pathway for so-called follow-on biologics. Differences between drugs and biologics will affect market outcomes in various ways. Conservative budget impacts are appropriate in the short run because fewer competitors will enter, and average prices will drop less than was the case following the Hatch-Waxman Act. Over the long term, intellectual property provisions will be important considerations for policymakers designing a pathway for follow-on biologics that balances price competition and innovation incentives.