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Strategies That Delay Market Entry of Generic Drugs
Abstract
Increasing prescription drug expenditures in the United States are primarily driven by high brand-name drug prices. Although generic competition helps lower drug prices, manufacturers of brand-name drugs often work to delay the availability of generic versions of their products. Strategies to forestall generic competition include patenting peripheral aspects of a drug or modified formulations that do not add clinical value, paying generic manufacturers to settle lawsuits challenging the validity of patents on brand-name drugs (“reverse payment” settlements), denying generic manufacturers access to drug samples necessary for bioequivalence testing, misusing risk evaluation and mitigation strategies, and filing citizen petitions with the US Food and Drug Administration (FDA). To address such tactics, the federal government can interpret existing patenting standards more strictly and promote certain types of patent challenges to ensure that patents are granted or upheld only for true innovations. Congress can enact pending legislation that would help discourage reverse payment settlements and compel brand-name manufacturers to share drug samples for bioequivalence testing. Finally, the FDA can provide earlier guidance on bioequivalence determinations for complex generic products and adopt the presumption that late-filed citizen petitions should be summarily rejected.
... To both recoup the costs of drug development and profit from a protected monopoly, innovating firms are incentivised to extend the life of patents. A common tactic is to file several secondary patents on the same drug to extend the 20-year period and impede market entry of generic competitors (Vokinger, Kesselheim, Avorn, & Sarpatwari, 2017). Another strategy is to prolong a drug patent through research on children. ...
... Slight alterations may be made to the original drug formula. For example, the new drug might rework the administration or dosage of the drug resulting in an extended -release formula or a rapid release formula (Collier, 2013).Though evergreening will require another patent application and clinical trials, it effectively deters the competition from producing a generic substitute, unless the FDA determines that the original innovator drug is of the same quality as the revised version (Bhat, 2005;Collier, 2013;Vokinger et al., 2017) . ...
... In 2013, the United States Supreme Court ruled that the Federal Trade Commission could sue patent holders for potential anti-trust violations for engaging in these agreements (New York Times, 2013). Though reverse-payment settlements are today less ubiquitous, they now often involve convoluted arrangements intended to conceal payment (Vokinger et al., 2017). ...
When a patent expires, innovator (brand-name) drugs lose their monopoly status and new generic competitors are free to enter the market. Theoretically, free market entry and exit should lead to a drop in the price of the innovator drug as per the tenets of perfect competition. Yet instead of prices decreasing, innovator drug prices are often minimally impacted by generic competition and the innovator continues to maintain both market power and market share – a phenomenon labelled the generic competitor paradox (Scherer, 1993) That the expected supply and demand dynamic is less pronounced in multisource drug markets, suggests that non-price considerations influence purchasing behaviour in multisource prescription drug markets. This dissertation focuses on the marketing theory of brand equity to rationalise the non-price competitive advantages that established prescription innovator (brand-name) drugs have over newer bioequivalent generic entrants. By analysing the prescribing habits of physicians, we find that brand equity confers a competitive advantage to the innovator drug: Brand equity is cultivated during the period of patent granted monopoly and creates a first-mover market advantage that is reinforced by the strategic creation of brand loyalty, which serves as a barrier to entry for generic substitutes.
... One key source of debate related to the exclusivity periods of drugs is that the primary patent covering each drug is often obtained shortly after the date of discovery, meaning a substantial fraction of its 20-year duration could have already lapsed by the time the drug has finished clinical trials, FDA review and is approved for widespread use [12,13]. To address manufacturers' concerns that they were unable to enjoy a full patent term, the Hatch-Waxman Act of 1984 created patent term restoration (PTR) [14][15][16][17][18][19], which allowed brand-name manufacturers to extend the duration of one key patent covering each prescription drug product to compensate for clinical trial and FDA review periods [14][15][16]. ...
... We labeled the first quarter of generic entry as the one in which a prescription for a therapeutically equivalent generic version of the brand-name drug appeared in Medicaid prescription data aggregated by the Centers for Medicare and Medicaid Services. We relied on Medicaid data to determine generic entry because actual generic entry can occur months or years after the generic drug receives FDA approval, for example, because of ongoing patent litigation or settlement agreements made with the affected brand name manufacturer [13,23,24]. We then calculated the effective market exclusivity period of each drug, defined as the difference between the quarter of FDA approval and the quarter of generic entry. ...
... Our data show that such policies are likely to have minimal impact in either direction owing to the prevalence of PTR and pediatric extensions that protect new drugs for 12 or more years. Other life-cycle management techniques that manufacturers use to extend exclusivity beyond this term include additional patents covering the same drug that were not granted PTR and litigation settlements with generic manufacturers [13]. ...
Patents temporarily protect brand-name drugs from generic competition, but some of the 20-year patent term is used up before marketing approval. To compensate for patent life lost to clinical testing and regulatory review, current law provides patent term restoration (PTR) of up to 5 years. Examining 170 top-selling drugs approved between 2000 and 2012, we found that 49% (83 drugs) received a PTR extension (median extension: 2.75 years) yielding a median total exclusivity period of 13.75 years, compared with 10.0 years for the 87 nonextended drugs. Because PTR substantially prolongs market exclusivity periods, policies that extend non-patent exclusivity periods (which generally run concurrently with patent exclusivity) for less than the extended patent terms of drugs will have little practical impact.
... Other strategies include withholding drug samples from generic manufacturers that they need to complete FDArequired bioequivalence testing or filing a citizen petition with the FDA, arguing that generic versions should not be approved because of safety concerns. 10 Because generic competition reduces drug prices, delays in generic drug entry can result in excess spending by payers and patients. To understand the financial impact of delayed availability, we identified a cohort of drugs predicted to lose market exclusivity and determined when a generic version actually entered the market. ...
... Although prior literature has identified several strategies that could delay generic entry, 10 our study identified patent litigation as the most common reason for delay, affecting 80 percent of the top fifteen drugs by total Medicaid spending in our cohort. When patent litigation was observed, most cases were settled out of court, which raises concerns that brand-name manufacturers may be offering incentives to generic manufacturers in exchange for terminating ongoing patent challenges. ...
Delays in market entry of generic drugs are common. This study sought to identify the prevalence of delayed entry, the reasons for the delays, and the delays' effects on Medicaid spending in a recent cohort of brand-name medications. We estimated excess Medicaid spending in 2010-16 in the delayed quarter-years after accounting for market average predictions of brand-name market share, ratios of generic to brand-name prices, and Medicaid rebates (60 percent for brand-name and 15 percent for generic drugs). Among sixty-nine brand-name drugs that were predicted to lose market exclusivity, generic entry occurred either before or within a quarter-year of the expected date for thirty-eight products (55 percent), was delayed by more than one quarter for twenty products (29 percent), and did not occur for eleven products (16 percent). For the thirty-one products (45 percent) for which generic entry was delayed by more than one quarter or did not occur, Medicaid spent an estimated excess of $761 million over seven years ($109 million annually). Patent litigation was the most common cause of generic entry delays. Policies that expedite the resolution of patent challenges are needed to ensure the timely entry of generic drugs.
... 29 Euphemisms for these strategies are ''life-cycle management'' or ''evergreening.'' 30 One strategy involves filing new patents for the coating, method of administration, or formulation of the drug before general patents expire. 31 These minimal modifications renew patent protection after a biochemical formula has expired, delaying the entry of generics. ...
... An FDA regulation to ensure safe drug distribution that can be used to hinder drug selling competition Clawback A profit incurred by an insurer when a copay exceeds the normal sale price Medication Assistance Program A discounted drug price provided directly to drug consumers by the original drug manufacturer Previous authorization A regulation designed to reduce spending by requiring Insurance approval before a nonformulary drug can be prescribed Step therapy A regulation designed to reduce spending by requiring a trial of a specific drug or drug class before alternative drugs will be reimbursed 37 REMS was designed to ensure safe usage of potentially harmful drugs 30 ; however, REMS can also be deployed to block drug sample access for generic competitor equivalence tests, reducing competition and leading to high prices. The unnecessary costs and lost price reduction opportunities created by REMS and similar programs have been projected to cost the US health care system $5.4 billion annually, 38 and it is unclear if the benefits of patented REMS programs outweigh their costs. ...
In the United States, drug costs account for approximately 10% of health care expenditures and are expected to grow over the next decade¹. Due to a combination of rising drug prices, increased out-of-pocket costs, and increased use of specialty drugs, a growing number of Americans cannot afford their medications. This issue is particularly relevant for the treatment of skin diseases, where retail prices of selected brand name dermatologic medications increased an average of 363% in real terms between 2009 and 2015, while the general and average pharmaceutical inflation rose only 11% and 23%, respectively2,3. In this article – part of a health policy series reviewing a wide-range of policy topics impacting clinical dermatology⁴– we provide an overview of how drug prices are set, with an emphasis on microeconomic factors that drive their complexity in the US, as well as discuss trends in drug pricing that are relevant to both the present and future delivery of dermatologic care.
... These new formulations "had no demonstrated incremental benefit on surrogate or patient outcomes" but generated more than $9 million in sales for the company over the next 8 years. 1 This latter set of activities is one type of "product hopping" and can help manufacturers prolong revenue streams relating to the underlying active ingredients of drugs. [4][5][6] New formulations of products may be protected by patents, and all receive a 3-year "new clinical investigation" regulatory exclusivity by the Hatch-Waxman Act, which prevents generic versions of the product from being approved by the U.S. Food and Drug Administration (FDA). 7 Complementary business strategies, such as product discontinuation, can augment the effect of product hopping. ...
... Notes: This figure shows the product lineage maps for the6 product portfolios that experienced generic entry during the study period. The reference products are shown diagonally as trunks with each new formulation branching directly downward. ...
Background:
After new prescription drugs reach the market, manufacturers sometimes create modified versions of them. These new formulations can expand patient treatment options, but they may also be protected by later-expiring patents or data exclusivities, which can lead to later generic entry for the new formulations compared with the original product.
Objective:
To quantify how frequently manufacturers introduce new formulations of existing drugs and how often these new formulations earn additional years of market exclusivity beyond that of the original product.
Methods:
Using a cohort design and FDA databases, we assessed how frequently manufacturers introduced new formulations of 17 new small-molecule drugs approved in 2002 and when generic entry for the new formulations and original product occurred.
Results:
Through 2017, nine (53%) drugs approved in 2002 had been connected to 21 new formulations, most (11/21, 53%) introduced before 2007. Generic entry was observed in 6 of 9 (67%) cases and occurred more than 2 years later for the new formulations in 3 of the cases.
Conclusions:
Our results suggest that the introduction of new formulations of brand-name drugs occurs in about half of cases and sometimes provides manufacturers with a lengthy period of additional market exclusivity beyond that of the original product.
Disclosures:
This work was funded by the Laura and John Arnold Foundation. Kesselheim and Sarpatwari also receive support from the Harvard-MIT Center for Regulatory Science and the Engelberg Foundation. Beall has nothing to disclose.
... Occasionally, generic entry may occur earlier than expected, such as when patents are invalidated or when generic firms launch products "at risk" before a judicial determination as to validity. In addition, market exclusivity periods can be extended through various strategies collectively referred to as "life-cycle management" or "evergreening" [13,14], which seek to delay generic entry past the expected date. For example, although the active ingredients of many drugs are patented shortly after they are discovered, manufacturers routinely obtain additional patents during the course of clinical development and even after approval from the Food and Drug Administration (FDA); these so-called secondary patents cover new formulations, uses, manufacturing methods, or peripheral features such as the coating of a pill [15,16]. ...
... The delays in generic entry associated with about half the drugs in our sample were attributable to a number of life-cycle management strategies, most prominently obtaining numerous secondary patents that generic manufacturers must then challenge [25,34,35]. Other life-cycle management strategies include settlements of patent litigation between brand-name and generic manufacturers that include promises not to market the product, restrictions on drug distribution in which brand-name manufacturers delay providing samples to the generic for the purpose of bioequivalence testing that can lead to FDA approval, and filing of citizen petitions of questionable merit that charge potential generics as not being sufficiently bioequivalent [13]. See the Appendix in Supplemental Materials found at https://doi.org/10. ...
Objectives: To develop and test a method for approximating generic entry of top-selling drugs. Methods: The procedure involved 1) identifying products’ key patents as those with a patent term restoration extension (whenever relevant) or otherwise as the first expiring patent listed in the US Food and Drug Administration's patent register, 2) determining whether the key patent had been extended through an associated pediatric extension, 3) identifying other regulatory exclusivities associated with the drug, and 4) categorizing key patents as active ingredient (or extended) patents versus secondary patents. The accuracy and precision of the procedure's predictions were then tested against a database containing the timing of generic entry for 170 top-selling drugs that lost market exclusivity between 2000 and 2012, on the basis of Medicaid data. Results: Overall, the procedure predicted a median market exclusivity period of 12.5 years (interquartile range [IQR] 7.25–14.5) compared with the median actual period of 12.5 years (IQR 8.5–14.75 years). Among the 131 drugs (77%) with active ingredient patents, the median predicted market exclusivity was 12.25 years (IQR 7.5–14.5) compared with a median actual period of 13.0 years (IQR 10.0–14.75). Among the 38 (22%) drugs protected only by secondary patents, the median predicted market exclusivity was 16.0 years (IQR 6.75–19.5), but the median actual market exclusivity was only 8.25 years (IQR 6.25–13.5). Conclusions: The procedure approximated median actual exclusivity with reasonable accuracy and precision for drugs with active ingredient patents, but substantially overestimated exclusivity for drugs with only secondary patents. © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR)
... 18 Brand-name manufacturers have developed numerous strategies to delay generic competition and extend their periods of monopoly protection. 19 For example, companies protect their drugs with thickets of patents related to the manufacturing, formulation, and use of the drug; generic drug makers must dispute these patents, and the resulting litigation can delay generic market entry. In other cases, brand-name drug makers introduce and heavily market slightly modified versions of their drug with additional patent protection, just before the original drug nears the end of its exclusivity period; this strategy is known as product hopping. ...
Recently, Congress has focused on reforms to address pharmacy benefit managers’ (PBMs) role in high drug prices for patients. Congress must not excessively restrict PBMs’ ability to negotiate with manufacturers; alternatively, reforms could be paired with other policies that address the high prices of brand-name drugs.
... A current study also shows that drug prices decrease to about 55% of brand-name prices when only two generic manufacturers are making the same product as a brand-name counterpart, alongside 33% with five manufacturers and 13% with 15 manufacturers . Despite these advantages, entry of generic drugs into the market is often delayed (Kesselheim 2017 Currently, alliances, such as that with Civica, are being formed to ensure that generics already on the market remain affordable (Vincz 2020). Further, many acts and bills have attempted to remedy the situation by facilitating more generics to enter the market (Wiske, Ogbechie, and Schulman 2015). ...
Introduction: Drug prices are a significant problem for the US healthcare system. Generic and biosimilar market competition reduces drug and biologic prices, results in substantial savings, and improves patient access and outcomes. As the costs of healthcare and prescription drugs continue to rise, the discussion about drug prices has taken a prominent place at the forefront of national discourse. This study assessed impacting trends in prices of generic, biosimilar, and reference products in the US. We also evaluated the effect of the Affordable Care Act (ACA) of 2010 on biologic prices. Methods: We extracted a list of the new generic drugs approved by the FDA from January 2013 to December 2018 from the FDA website and the acquisition cost from the Centers for Medicare and Medicaid Services (CMS) National Average Drug Acquisition Cost (NADAC) database. We extracted a list of biosimilar products approved by the FDA as of September 2021 from the FDA website and Average Sales Price (ASP) from the 1st quarter of 2005 to the 3rd quarter of 2021 from the CMS website database. We segmented the data using inflection point detection and conducted piecewise linear regression to find differences in the trends for the segments defined by the inflection points. We used R Project for Statistical Computing version 3.6.1 for the analysis. Results:The median generic prices at market entry represented 65.7% of the brand prices and 26.0% three years after generic entry. The median reference drug prices increased by 1.0% per month in the pre-generic period, remained constant in the generic entry period (3 months before to 6 months after generic entry), and increased by 0.4% per month in the post-generic period. Biosimilar prices represented 75% of the reference biologic prices at market entry. The median prices of reference biologics declined after biosimilar competition, while the prices of biologics without competition increased (94.5 vs. 163.6, p Conclusions: Market competition significantly reduced drug and biologic prices and affected the price trends of reference products. The prices of drug and biologic reference products decreased after biosimilar market entry. Prices of biologics significantly increased after the implementation of the ACA.
... Brand-name manufactures have an incentive to engage in strategies to delay the introduction of generic drugs and reduce competition. 26 Policies to encourage generic entry, such as the 1984 ...
Importance
The high and increasing expenditures for prescription medications in the US is a national problem.
Objective
To explore the association of generic statin competition on relevant use and cost savings and to provide use and expenditure trends for all available statins for private and public payers and for out-of-pocket spending.
Design, Setting, and Participants
This survey study evaluated data from the January 1, 2002, to December 31, 2018, Medical Expenditure Panel Survey by using a difference-in-differences analysis. Participants included noninstitutionalized individual statin users. Data were analyzed from November 1, 2020, to March 30, 2021.
Exposures
The market entry of 5 generic statin medications (atorvastatin, rosuvastatin, simvastatin, lovastatin, and pravastatin).
Main Outcomes and Measures
National- and individual-level reductions in the annual number of statin purchases and total expenditures across private insurance, public insurance (Medicaid and Medicare), and out-of-pocket spending (presented in 2018 US dollars).
Results
Between January 1, 2002, and December 31, 2018, an average of 21.35 million statins (95% CI, 16.7-25.5 million) were purchased annually, with an average total annual cost of $24.5 billion (95% CI, $18.2-$28.8 billion). The number of brand-name statin purchases decreased by 90.9% (95% CI, 56%-98%) nationally and 27.4% (95% CI, 13%-40%) individually after the end of market exclusivity. Among major payers, the end of market exclusivity was associated with individual cost savings of $370.00 (95% CI, $430.70-$309.20) for private insurers, $281.00 (95% CI, $346.80-$215.30) for Medicare, $72.34 (95% CI, $95.22-$49.46) for Medicaid, and $211.90 (95% CI, $231.20-$192.50) for out-of-pocket spending. Combining all payers, the decrease translates to $925.60 (95% CI, $1005.00-$846.40) of annual savings per individual and $11.9 billion (95% CI, $10.9-$13.0 billion) for the US.
Conclusions and Relevance
Results of this survey study suggest that full generic competition of statins was associated with significant cost savings across all major payers within the US health care system.
... In this study, we found delayed time to entry of generic drugs in the long run, particularly for non-NDAs in injection forms and biologics, and this finding partially associated with market attractiveness. In this context, the role of the MFDS to address the delayed availability of generic drugs could be revisited (31,37). ...
Introduction: Generic entry is a well-known driver of competition and cost containment.
Objectives: We aim to measure the market exclusivity of originator drugs and to determine what influences the entry of generics in South Korea.
Methods: A list of originator drugs approved by the authority from 2000 to 2013 and their corresponding generics were paired. An event history model was applied for a statistical estimation for the duration until generic entry and to identify abbreviating or prolonging factors on the duration.
Results: A total of 2,061 pairs of originator and generics were identified. The market exclusivity for the originator drugs, including NDAs and non-NDAs, has not notably changed. However, competition among non-NDAs was less common than we expected. We found delayed time to entry of generics in the long run, particularly for non-NDAs in injection forms and biologics, and this finding is partially associated with market attractiveness.
Conclusion: The authority should address the delayed availability of certain types of generic drugs. The government could provide information on off-patent pharmaceuticals with no generic competition, designate their corresponding submissions as prioritized in the review process, and provide additional market exclusivity when entering the market via a long period of exclusivity.
... 16 One 2018 report found that 89% of these patent applications were filed after adalimumab was on the market, and 49% were filed after the first patent expired in 2014. 34 This strategy of creating a wall of patents to protect assets 34,35 is known as developing a "patent thicket." 16 AbbVie sued the manufacturers of adalimumab biosimilars, including Amgen, Boehringer Ingelheim, Mylan, Pfizer, Samsung Bioepis, and Sandoz, for patent infringement, with settlements having been reached in all but one case. ...
Biologics are among the most expensive prescription drugs in the United States, posing significant barriers to patient access to necessary treatments. An abbreviated approval pathway for biosimilars, near-identical versions of biologics made by different manufacturers, was created by Congress in 2010 to stimulate competition in hopes of driving down costs and expanding access. However, as of February 2019, only 17 biosimilars have been approved, with only 7 currently on the market. Of the few biosimilars currently available to patients, overall utilization has been limited. This article examines the current landscape of the biosimilar market, characterizes tactics employed by biologics manufacturers to delay market entry and deter prescribing of biosimilars, and assesses ethical issues related to increasing the adoption of biosimilars.
... The United States provides drug companies with the strongest patent protections in the world, but legal strategies in the pharmaceutical industry, such as patenting peripheral aspects of a drug that extend exclusivity rights beyond the original patent and delay generic and biosimilar competition, abuse that liberty. 21 The large discrepancy between the prices of drugs purchased in the United States and drugs purchased in the rest of the world 2 is often attributed to the legal inability of public and private insurers to negotiate drug prices. Innovative solutions, such as the Institute for Clinical and Economic Review's value-based price benchmark, 22 have the potential to find appropriate price points for patients while rewarding drug manufacturers that produce transformative products. ...
Importance
High and continually increasing pharmaceutical drug spending is a major health and health policy concern in the United States.
Objective
To demonstrate trends in prices among popular brand-name prescription drugs.
Design, Setting, and Participants
This economic evaluation of drug prices focuses on 49 top-selling brand-name medications in the United States. Pharmacy claims data from January 1, 2012, through December 31, 2017, were obtained from Blue Cross Blue Shield Axis, a database that includes data from more than 35 million individuals with private pharmaceutical insurance. Drugs that exceeded $500 million in US sales or $1 billion in worldwide sales were examined.
Main Outcomes and Measures
The median sum of out-of-pocket and insurance costs paid by patients or insurers for common prescriptions, presented annually and monthly, was the primary outcome.
Results
In total, 132 brand-name prescription drugs were identified in 2017 that met the inclusion criteria. Of this total, the study focused on 49 top-selling drugs that exceeded 100 000 pharmacy claims. Substantial cost increases among these drugs was near universal, with a 76% median cost increase from January 2012 through December 2017, and almost all drugs (48 [98%]) displaying regular annual or biannual price increases. Of the 36 drugs that have been available since 2012, 28 (78%) have seen an increase in insurer and out-of-pocket costs by more than 50%, and 16 (44%) have more than doubled in price. Insulins (ie, Novolog, Humalog, and Lantus) and tumor necrosis factor inhibitors (ie, Humira and Enbrel) demonstrated highly correlated price increases, coinciding with some of the largest growth in drug costs. Relative price changes did not differ between drugs that entered the market in the past 3 to 6 years and those that have been on the market longer (number of drugs, 13 vs 36; median, 29% increase from January 2015 through December 2017; P = .81) nor between drugs with or without a Food and Drug Administration–approved therapeutic equivalent (number of drugs, 17 vs 32; median, 79% vs 73%; P = .21). Changes in prices paid were highly correlated with third-party estimates of changes in drug net prices (ρ = 0.55; P = 3.8 × 10⁻⁵), suggesting that the current rebate system, which incentivizes high list prices and greater reliance on rebates, increases overall costs.
Conclusions and Relevance
The growth of drug spending in the United States associated with government-protected market exclusivity is likely to continue; greater price transparency is warranted.
... 3 Brand-name drug manufacturers also develop strategies in advance of generic entry to minimize revenue loss, 4 such as taking steps to delay generic entry and introducing new products to buoy income and meet investor expectations. 5 When does generic entry occur? A brand-name drug's market exclusivity term is primarily determined by its patents. ...
... In addition, another interesting topic for future investigation is the assessment of the therapeutic value of octreotide in the treatment of advanced pancreatic cancer, Figure 7 Advantages of fully exploiting a marketed drug's therapeutic potential and advantageous features of drug repositioning in oncology. Notes: The multiyear clinical experience of the use of a marketed drug with anticancer properties not currently exploited as a direct antineoplastic agent, possible multiple therapeutic benefits (eg, octreotide exhibits both direct anticancer activities and palliates symptoms associated with bowel obstruction in patients with advanced malignancies), circumvention of the time-consuming process of launching a newly discovered pharmaceutical on the market, 140 as well as the well-described mechanism of action that may involve pleiotropy (eg, chloroquine may function both as a Par4 secretagogue or a DNA-repair inhibitor), in striking contrast to "targeted" anticancer bulletins that have proven to be a less promising therapeutic approach than initially expected, at least in some cases, 141,142 are numbered among the major advantageous features of repositionable agents in comparison with newly designed/discovered agents exhibiting antitumor function. These features will possibly tilt the scales in favor of commercially available agents exhibiting antitumor function in the fight against cancer. ...
Pleiotropy in biological systems and their targeting allows many pharmaceuticals to be used for multiple therapeutic purposes. Fully exploiting the therapeutic properties of drugs that are already marketed would be highly advantageous. This is especially the case in the field of oncology, where the ineffectiveness of typical anticancer agents is a common issue, while the development of novel anticancer agents is a costly and particularly time-consuming process. Octreotide and chloroquine are two pharmaceuticals that exhibit profound antitumorigenic activities. However, the current therapeutic use of octreotide is restricted primarily to the management of acromegaly and neuroendocrine tumors, both of which are rare medical conditions. Similarly, chloroquine is used mainly for the treatment of malaria, which is designated as a rare disease in Western countries. This limited exploitation contradicts the experimental findings of numerous studies outlining the possible expansion of the use of octreotide to include the treatment of common human malignancies and the repositioning of chloroquine in oncology. Herein, we review the current knowledge on the antitumor function of these two agents stemming from preclinical or clinical experimentation. In addition, we present in silico evidence on octreotide potentially binding to multiple Wnt-pathway components. This will hopefully aid in the design of new efficacious anticancer therapeutic regimens with minimal toxicity, which represents an enormous unmet demand in oncology.
... First, national regulators should streamline the generic drug approval process. [93,226] In response to recent price hikes in the United States, Kesselheim et al called for regulators to prioritize applications from manufacturers trying to bring to market a generic medicine sold by three or fewer firms. [74,212,227] This would put downward pressure on prices and make it harder for individual companies to have much influence over prices. ...
Background and importance: Rising drug prices are putting pressure on health care budgets. Policymakers are assessing how they can save money through generic drugs. Objective: The aim of this Ph.D. was to explore issues relating to the prices and usage of generic medicines in high- and middle-income countries in five articles. This was done using quantitative and qualitative methods, including price and Herfindahl-Hirschman indexes, difference-in-differences regression analyses, semi-structured stakeholder interviews, and literature reviews. As a Ph.D. “thesis by papers”, each of the five articles should be read as a stand-alone piece. However, the thesis presents an overarching narrative, outlined at the end of Chapter 1. Novelty and empirical contribution: My original contributions to knowledge are: (i) updated analyses of generic drug policies, prices, and usage rates in high-income countries, based on a large, representative sample of generic medicines from 2013 (Chapters 2 and 3); (ii) evidence on the impact of a pharmaceutical tendering system on medicines prices, demand, and competition over a 15-year period (Chapter 4); (iii) quantitative data on the impact of therapeutic tendering on drug spending and prices (Chapter 5); and (iv) qualitative data on how a country can move from a fragmented health-care system to a single-payer one, using tendering as the basis for a comprehensive drug-benefit plan (Chapter 6). Key findings: The prices and market shares of generics varied widely across Europe. For example, prices charged by manufacturers in Switzerland were, on average, more than 2.5 times those in Germany and more than 6 times those in the United Kingdom, based on the results of a commonly used price index. However, the results varied depending on the choice of index, base country, unit of volume, method of currency conversion, and therapeutic category. The results also differed depending on whether one looked at the prices charged by manufacturers or those charged by pharmacists. The proportion of prescriptions filled with generics ranged from 17% in Switzerland to 83% in the United Kingdom. The results of the first two studies indicated that the countries which used tender or tender-like systems to set generic drug prices in retail pharmacies (ie, Denmark, Germany, the Netherlands, and Sweden) had among the lowest prices among the countries included in the studies. Tendering can be an effective policy to procure essential medicines at low prices, based on analysis of data from South Africa and Cyprus. For instance, the average prices of antiretroviral therapies, anti-infective medicines, small-volume parenterals, drops and inhalers, solid-dose medicines, and family-planning agents dropped by roughly 40% or more between 2003 and 2016 in South Africa. Many tender contracts in South Africa remained competitive over time, based on the Herfindahl-Hirschman results, with some notable exceptions. However, the number of different firms winning contracts decreased over time in most tender categories. Also, there were large discrepancies between the drug quantities the health ministry estimated it would need to meet patient demand and the quantities the ministry went on to procure during tender periods. In South Africa, the introduction of therapeutic tendering was associated with an estimated 33% to 44% reduction in the prices of solid-dose drugs in 2014. National governments in countries aiming to introduce national health systems (eg, Cyprus and South Africa) will need to adapt their tendering systems and other pharmaceutical policies during transition periods. Future research directions: More research is needed to better understand the drivers of differences in generic drug prices between countries. It is also important to examine why there are large differences in the prices of drugs in various therapeutic areas, both within and between countries. Also, data from more countries, especially low- and middle-income ones, are needed to determine which features of tendering systems are associated with lower prices. Future studies should re-examine the South African therapeutic tendering system once data from more post-intervention periods are available, possibly using other research designs like interrupted time-series models (ie, segmented regression analysis). Policy implications: Price indexes are useful statistical approaches for comparing drug prices across countries, but policymakers should interpret price indexes with caution given their limitations. This thesis offers useful data for policymakers using, or planning to introduce, tendering systems, especially in countries aiming for universal health coverage, like Cyprus (Chapter 6) and South Africa (Chapters 4 and 5).
Importance
The Federal Trade Commission’s (FTC) oversight role in the pharmaceutical market is critical to the health of patients and the health care system. This study characterized the FTC’s policy on the pharmaceutical market in recent decades, identifying the types of actions it has favored, barriers it has faced, and authorities that remain untested.
Objective
To review FTC legal actions in the pharmaceutical market from 2000-2022.
Evidence Review
Legal actions were determined through manual review of search results from the FTC’s online Legal Library as well as a 2023 FTC report on pharmaceutical actions. The alleged misconduct, type of legal action taken, timing, and outcome were collected from press releases, complaints, orders, and other legal documents.
Findings
From 2000-2022, the FTC challenged 62 mergers, brought 22 enforcement actions against allegedly unlawful business practices, and made 1 rule related to pharmaceuticals. Alleged misconduct in enforcement actions involved anticompetitive settlements in patent litigation (n = 11), unilateral actions by brand manufacturers to delay generic competition (n = 6), noncompete agreements (n = 4), and monopolization (n = 3), with 10 outcomes involving monetary payment, totaling $1.6 billion. Of the 62 mergers the FTC challenged, 61 were allowed to continue, 58 after divesting certain drugs to third-party competitors. The FTC’s reliance on drug divestitures decreased from 18 drugs per year from 2000-2017 to 4.3 per year from 2017-2023.
Conclusions and Relevance
The FTC brought about 1 enforcement action and 3 merger actions per year against pharmaceutical manufacturers from 2000-2022, pursuing a small fraction of the estimated misconduct and consolidation in the pharmaceutical marketplace. Although the FTC faces substantial legal and practical limitations, important tools remain untested, including a rule defining “unfair methods of competition,” that may allow it to more effectively prevent repetitive patterns of anticompetitive behavior.
Importance
Brand-name drugs are sold at high prices in the US during market exclusivity periods protected by patents. Multiple overlapping patents protecting a drug are known as patent thickets and can effectively delay the emergence of price-lowering generic competition for many years.
Objective
To evaluate the composition of patent thickets of 10 top-selling prescription drugs in the US and compare the characteristics of drug patents filed during development with those filed on these products after US Food and Drug Administration (FDA) approval.
Design and Setting
This cross-sectional study examined US patent thickets of the 10 prescription drugs with the highest US net sales revenue in 2021 using information on issued patents and patent applications as of June 30, 2022, obtained from a public database by the Initiative for Medicines, Access, and Knowledge. Data were analyzed from September 2022 to June 2023.
Main Outcomes and Measures
Prevalence of patents filed before and after FDA approval; types of claims present in issued patents (ie, chemical composition, method of use, process or synthesis, formulation, and delivery device); and patent thicket density (number of active patents at a given time).
Results
The 10 top-selling prescription drugs in the US for 2021 included 4 small-molecule drugs and 6 biologics. These 10 drugs were linked to 1429 patents and patent applications: 742 (52%) issued patents, 218 (15%) pending applications, and 469 (33%) abandoned applications. Almost three-quarters of patent applications (1028 [72%]) were filed after FDA approval. The postapproval proportion was higher for biologics (80%) than for small-molecule drugs (58%). Postapproval filing of patent applications peaked in the first 5 years after FDA approval for small-molecule drugs and 12 years after FDA approval for biologics. Of 465 patents issued for applications filed after FDA approval, 189 (41%) had method of use claims, 127 (27%) had formulation claims, and 103 (22%) had process or synthesis claims, while 86 (19%) had chemical composition claims and 46 (10%) had device claims. Patent thicket density peaked 13 years after FDA approval, at which time these 10 drugs were protected by a median (IQR) of 42 (18-83) active patents, 66% of which were filed after FDA approval.
Conclusions and Relevance
This study found that among the 10 top-selling prescription drugs in the US in 2021, patents filed after FDA approval and containing claims covering aspects other than the active ingredient of the drug contributed to patent thickets. Scrutiny of patent applications and of patents filed after FDA approval is needed to facilitate timely generic or biosimilar competition.
This cross-sectional study identified the prevalence of patents on risk evaluation and mitigation strategies and their association with delaying generic competition.
Objectives
Brand-name drug manufacturers can market or license authorized generics (AGs), which are the same product sold under a generic name. By contrast, independent generics (IGs) are made by other manufacturers. The brand-name manufacturer of entacapone, a treatment for Parkinson’s disease, established 4 AGs before IGs emerged. We used this case study to understand how AGs can affect the length of brand-name exclusivity and robustness of generic competition.
Methods
Using public Food and Drug Administration and court records, we identified the regulatory and legal history for generic entacapone products marketed through 2021. We used Medicare Part D data to estimate trends in use, prices, and spending on entacapone products from 2011 to 2020, comparing actual spending with projected spending if IG competition had begun after expiration of the key patent protecting entacapone (October 2013) and prices had fallen consistent with levels observed for other generic drugs.
Results
From 2012 to 2014, 3 potential entacapone IG manufacturers instead launched AG versions after settlement agreements with the brand-name manufacturer; the brand-name manufacturer additionally introduced its own AG. Four different IG versions were marketed beginning in 2015. From 2011 to 2020, average Medicare prices declined by 62%, less than the projected 74% to 92% price decline expected for a drug with 8 generics. Over this period, Medicare spent $1.1 billion on entacapone products, which could have been reduced by an estimated $137 to $449 million through typical IG competition.
Conclusions
The case of entacapone demonstrates how licensing multiple AGs in place of IG competition can increase spending. Government regulators should more rigorously monitor AGs to prevent such strategies.
New Drugs, Fair Prices addresses the important question of how we might get the innovative new medicines we need at prices we can afford. Today, this debate is impassioned but sterile. One side calls for price controls, discounting their impact on investment in innovation. The other points to miraculous new therapies, disregarding their affordability and social inequity. This polarized argument creates more heat than light, threatening the social contract between the industry and society on which pharmaceutical innovation depends. This ground-breaking book takes a wholly new perspective on the issue and raises the debate to a more informed and productive level. Drawing on interviews with more than 70 experts across the pharmaceutical innovation world and combining a diverse literature from scientific, political, economic and business domains, it describes how a sustainable and affordable supply of new medicines is possible only by balancing pharmaceutical innovation’s complex, adaptive ecosystem. By considering how each of the ecosystem’s seven habitats work and interact with the others, it makes a comprehensive set of recommendations for achieving that ecosystem balance. The core message of New Drugs, Fair Prices is important to anyone who ever has needed or will ever need a medicine: We can have a sustainable supply of new medicines that are both innovative and affordable if we manage the pharmaceutical innovation ecosystem intelligently.
Objectives
Substitution of brand-name drugs with less expensive, equally effective interchangeable generics is an important strategy for promoting adherence and controlling prescription drug spending. US state laws govern generic substitution, but there is variability among states in how these laws are designed. We aimed to determine how different features of state laws regulating generic substitution are associated with use of generic drugs.
Methods
Using national claims databases, we studied individuals with commercial insurance or Medicare Advantage plans who newly initiated one of 34 prescription drugs during the year after new generic competition (2017-2018) to determine any association between generic use and 3 different features of state laws. We used multivariable logistic regression to adjust for demographic and clinical characteristics.
Results
Of 502 763 individuals who initiated one of the drugs, 409 856 (81.6%) received a generic version. Those in states requiring patient consent or notification had lower use of generics (81.1% vs 82.9%; adjusted odds ratio 0.89; 95% confidence interval 0.87-0.91; P < .001). By contrast, mandating versus permitting generic substitution and protecting pharmacists from liability did not appear to have significant effects.
Conclusions
In this study of commercially insured and Medicare Advantage patients, patients in states requiring consent or notification for pharmacists to substitute Food and Drug Administration–certified interchangeable generics had lower use of generics. Laws in 39 states plus the District of Columbia could be amended to improve use of inexpensive and equally effective generic drugs.
PURPOSE
Generic competition can be delayed if brand-name manufacturers obtain additional patents on supplemental uses. The US Food and Drug Administration allows generic drug manufacturers to market versions with skinny labels that exclude patent-protected indications. This study assessed whether use of generic versions of imatinib varied between indications included and excluded from the skinny labels.
METHODS
In this cross-sectional study, we identified adult patients covered by commercial insurance or Medicare Advantage plans who initiated imatinib from February 2016 (first generic availability) to September 2020. Generic versions were introduced with skinny labels that included indications covering treatment of chronic myelogenous leukemia (CML) but excluded treatment of gastrointestinal stromal tumors (GISTs) because of remaining patent protections. Logistic regression was used to determine whether use of generic versus brand-name imatinib differed between patients with a diagnosis of CML or GIST, adjusting for demographics, insurance type, prior use of brand-name drugs, and calendar month.
RESULTS
Among 2,000 initiators, 934 (47%) had CML and 686 (34%) had GIST. Within 3 years after generics entered the market, more than 90% of initiators in both groups used generic imatinib. Initiation of generic imatinib was slightly lower among patients with GIST than among patients with CML (85% v 88%; adjusted odds ratio 0.56; 95% CI, 0.39 to 0.80; P ≤ .001).
CONCLUSION
Generic versions of imatinib were dispensed frequently for indications both included (CML) and excluded (GIST) from the skinny labeling, although patients with GIST were slightly less likely to receive a generic version. The skinny labeling pathway allowed generics to enter the market before patent protection for treating patients with GIST expired, facilitating lower drug prices.
Brand-name prescription drug manufacturers use various strategies to extend their market exclusivity periods by delaying generic or biosimilar competition. Recent Congressional legislation has targeted four such tactics. We analyze these proposals and assess their likely effect on competition in the U.S. drug market.
Objectives
In the United States, brand-name prescription drugs remain expensive until market exclusivity ends and lower-cost generics become available. Delayed generic drug uptake may increase spending and worsen medication adherence and patient outcomes. We assessed recent trends and factors associated with generic uptake.
Methods
Among 227 drugs facing new generic competition from 2012 to 2017, we used a national claims database to measure generic uptake in the first and second year after generic entry, defined as the proportion of claims for a generic version of the drug. Using linear regression, we evaluated associations between generic uptake and key drug characteristics.
Results
Mean generic uptake was 66.1% (standard deviation 22.1%) in the first year and 82.7% (standard deviation 21.6%) in the second year after generic entry. From 2012 to 2017 generic uptake decreased 4.3% per year in the first year (95% confidence interval, 2.8%-5.8%, P < .001) and 3.2%/year in the second year (95% confidence interval, 1.2%-5.1%). Generic uptake was lower for injected than oral drugs in the first year (38.5% vs 70.0%, P < .001) and second year (50.3% vs 86.9%, P < .001). In the second year, generic uptake was higher among drugs with an authorized generic (86.1 vs 80.1%, P = .045) and those with ≥3 generic competitors (87.7% vs 78.6%, P = .055).
Conclusion
Early generic uptake decreased over the past several years. This trend may adversely affect patients and increase prescription drug spending. Policies are needed to encourage generic competition, particularly among injected drugs administered in a hospital or clinic setting.
Providing the population of Ukraine with quality, effective and, at the same time, economically affordable medicines is a priority task of the healthcare system. Taking into account the relatively low cost of their development generic drugs are available to the majority of the country’s population; thus, bioequivalence studies are needed to obtain data on their efficacy and safety. Ukraine is currently in the process of harmonizing domestic regulatory requirements for generic drugs and conducting bioequivalence studies with global ones. Therefore, it is important to find out the differences in approaches to the registration of generics and studies of their bioequivalence in Ukraine and other countries. Another important aspect is to provide the policy of “transparency” of bioequivalence research results, which contributes to the use of better drugs. Aim. To analyze domestic and global approaches to the organization of the bioequivalence research and provide the policy of “transparency” of their results. Materials and methods. A comparative analysis of approaches to drug registration, requirements for generic drugs and bioequivalence studies and ways to provide the policy of “transparency” of their results in Ukraine, the United States and the European Union was conducted. Results. The analysis has revealed that the methods of registration of drugs in Ukraine, the United States and the EU are the same. Approaches to providing the “transparency” of the results of bioequivalence studies differ since in Ukraine the publication of such information is not mandatory and is at the discretion of pharmaceutical manufacturers. Conclusions. Domestic regulatory requirements for assessing generic drugs are harmonized with the world ones. Today, there is a need to introduce a mandatory requirement for the publication of bioequivalence studies, and it will contribute to providing an effective “transparency” policy.
Modified versions of existing drugs can substantially increase costs for patients and the health care system if the new version does not offer meaningful clinical improvement.
Brand-name drug manufacturers in the US use several strategies to delay generic competition,¹ including obtaining a thicket of patents to protect beyond a drug’s active ingredient and original use.² Such patents can cover use of the drug for supplemental indications that the US Food and Drug Administration (FDA) approves after a medication is already on the market.
Background: The nature of competition within the pharmaceutical sector has received a great deal of attention from policymakers and researchers. This is the first study to comprehensively analyze long listed single-source products within the South Korean market.
Methods: Long listed single-source products are defined as pharmaceutical drugs that are available in the market for at least 8 years, without competition. We analyzed the determinants that lead to long listed single-source products in the market, and then evaluated their impact on health systems by examining the subsequent price responses of manufacturers.
Results: Based on the number of drugs and their market values, pharmaceuticals categorized as long listed single-source products constitute a substantial portion of the market. Characteristics of the market are closely associated with generic entrants. In particular, the market size of a substance is associated with generic entrants, while the price of a brand-name drug is related to being long listed single-source products.
Conclusions: Our analysis supports the creation of a regulatory and/or reimbursement system in order to support robust and effective competition within the marketplace. The first step towards rationalizing the system is to provide widespread information on drugs with limited competition or no competition.
Importance
Market exclusivity for daily injections of glatiramer acetate, a disease-modifying therapy for multiple sclerosis, expired in 2015. In 2014, the manufacturer launched an alternate 3-times-weekly version that was widely adopted, sustaining market dominance of brand-name glatiramer until late 2017.
Objective
To estimate excess US spending associated with the transition from daily to 3-times-weekly glatiramer.
Design, Setting, and Participants
This economic evaluation estimated total US glatiramer spending from January 1, 2011, to June 30, 2019, using a national cohort from 3 data sources that collectively represent approximately 40% of the US glatiramer market: Medicare Part D, Medicaid, and a claims database of commercially insured and Medicare Advantage patients.
Exposures
Calendar quarter.
Main Outcomes and Measures
Outcomes were quarterly US glatiramer spending, estimated as price × use. Manufacturer list prices for generic products and estimates of net (postrebate) prices for brand-name products were used. Linear regression and interrupted time series models were used to compare spending trends in 3 periods: before generic competition (2011-2015), during generic competition for daily glatiramer (2015-2017), and during generic competition for daily and 3-times-weekly glatiramer (2017-2019).
Results
From 2011 to 2015, US glatiramer spending increased to $962 million per quarter and did not decrease with generic competition of only daily glatiramer (2015-2017). After generic competition began for 3-times-weekly glatiramer in 2017, prices decreased by 47% to 64%, and spending decreased to $508 million per quarter in 2019 (P < .001 for slope). The delay in decreased spending from 2015 to 2017 was associated with excess spending of $4.3 billion to $6.5 billion.
Conclusions and Relevance
These findings suggest that 2.5 years of delayed generic competition related to introduction of a new version of branded glatiramer acetate was associated with $4.3 billion to $6.5 billion in excess spending. Extended market exclusivity from introducing a new version of an existing brand-name drug can yield manufacturer returns out of proportion to the level of investment or risk involved; more limited incentives could encourage incremental innovations to existing drugs at a lower societal cost.
Brand‐name drugs have periods of market exclusivity before generic competition begins. Due to high brand‐name drug prices charged during this period, market exclusivity is an important determinant of US prescription drug spending. We used claims data to estimate the market exclusivity period for 264 small molecule and 4 biologic drugs that faced new generic or biosimilar competition from 2012‐2018. Exclusivity periods were longer for biologics compared to new small molecule drugs (median 21.5 vs 14.4 years, p=0.02), longer for drugs with annual revenue <$75 million compared to those with revenue ≥$500 million (16.6 vs 14.2 years, p=0.006), and shorter in cases for which the first generic was granted 180 days of exclusivity, which is an incentive designed to expedite generic competition (14.1 vs 15.9 years, p<0.01). Modified versions of existing products had shorter exclusivities than new drugs (9.9 vs 14.5 years, p < 0.01), with variation by route of administration, therapeutic area, and use of expedited approval pathways. Exclusivity periods for new drugs ranging from 13‐17 years are similar to older estimates, but longer exclusivity among the small number of biologics in the cohort raises concern that overall median exclusivity may lengthen in the future since biologics represent a larger fraction of new drug approvals over the last decade than they did the previous decade. Unnecessarily long exclusivity periods delay patient access to lower‐priced medications, and policymakers should consider options to encourage timely competition, particularly among biologic drugs.
Our objective was to compare expected and observed biosimilar and generic entry dates for a recent cohort of brand‐name drugs. Therefore, we estimated expected biosimilar and generic entry dates for all 328 new drugs approved by the Food and Drug Administration (FDA) between 2000‐2012, which we defined as the later of the expiration of the key patent term or statutory exclusivity (12 years for biologics, 5 years for small‐molecule drugs not indicated for a rare disease, and 7 years for small‐molecule drugs indicated for a rare disease (plus 6 months if a pediatric extension had been granted). For drugs with expected entry prior to 2019, we calculated the proportion with observed biosimilar or generic entry. The expected biosimilar entry dates were estimated to be a median of 12.3 years (interquartile range [IQR]: 12.0‐14.0, n=60) after FDA approval. The 12‐year biologic statutory exclusivity period comprised 98% of the median expected protection period. By contrast, expected generic entry was estimated to be a median of 12.2 years (IQR: 8.4‐14.0, n=268), or 7.2 years after the 5‐year small‐molecule statutory exclusivity (59% of the total expected market protection period). By 2019, observed biosimilar entry occurred in 12% of cases (3/25) and observed generic entry in 65% (101/155). We concluded that expected US market exclusivity periods are similar for biologic and small‐molecule drugs. Statutory exclusivity plays a more substantial role in market exclusivity protection for biologics. Biosimilar competition, currently lagging far behind generic competition, will likely increase as the biosimilar market becomes established.
Event studies of stock price movements have been used to assess the anticompetitive impact of ‘reverse-payment’ settlement of patent disputes in the drug industry. Evidence for an anticompetitive effect is found when financial markets reward a brand manufacturer with larger stock market capitalization – signaling the agreed upon generic entry date was more profitable (i.e. later) than investors’ expectations. In practice, reverse-payment cases can involve multiple generic competitors and settlements. This paper considers how event-study methodology applies in such cases, with a study of the stock price movements of Cephalon, manufacturer of the drug Provigil. Cephalon entered into four patent litigation settlements with potential generic competitors over a two-month period beginning in December 2005. Event study methods can readily be applied to such a case. Cephalon’s total increase in stock value across four narrow windows around each settlement totaled over $1.0 billion, indicating the agreements delayed generic entry beyond the market's expectation.
Background:
Successful first-generation drugs can be converted with small alterations to "second-generation drugs," which are cheaper to develop and may pose less financial risk for manufacturers due to already validated action mechanism and a well-defined consumer market.
Methods:
We found four classes of cancer drugs for first- and second generation products approved in the US: BCR-ABL tyrosine kinase inhibitors (TKI) for treatment of CML, ALK + TKI for NSCLC, CD20 monoclonal antibodies for CLL, and HER2 monoclonal antibodies for breast cancer. We analyzed the characteristics of the clinical trials and the approval pathways for these 14 drugs.
Results:
First-generation and 4 out of 5 s-generation BCR-ABL TKI drugs were granted expedited approval, while all drugs were approved based on single-arm trials. Both ALK + TKI drugs were based on single-arm trials and expedited approval. The first-generation CD20 monoclonal antibody drug was approved based on single-arm trials, and one of the second-generation drugs had pivotal trials that were randomized. All benefited from expedited approval. All HER2 monoclonal antibodies in the sample were based on randomized trials and expedited pathways.
Conclusion:
Second-generation TKI and monoclonal antibodies were often approved through expedited regulatory pathways and studied in single-arm trials. This helps to facilitate the approval for earlier use by patients, but is also associated with greater risk of post-approval safety-related labeling changes or unanticipated adverse events.
We have seen a sharp increase in cancer drug prices in recent years, far exceeding the rates of inflation. This increasing cost of cancer drugs has many adverse consequences not only for the economy of the country but also in clinical outcomes of cancer patients, a phenomenon referred to as “financial toxicity.” Indeed, the increasing cost of cancer drugs is no longer just a policy issue; it is also a clinical issue with clinical consequences such as increased risk of mortality, poor quality of life, and lack of adherence to medications among others. In this chapter, I explore the causes and consequences of high cancer drug prices in detail and will also walk the readers through different strategies that have been proposed to control these costs. Indeed, each solution strategy has its own challenges, but not doing anything is no longer a sustainable strategy. We owe it to our patients that they are able to take the cancer drugs that help them live longer or live better without having to worry about being bankrupt during the course of treatment.
In this issue of JAMA, Rollman et al report concerning findings regarding US Food and Drug Administration (FDA) stewardship of the Risk Evaluation and Mitigation Strategies (REMS) system,¹ raising further uncertainty as to its utility in ensuring the safe use of prescription drugs. Created under the 2007 FDA Amendments Act, this system was intended to address the FDA’s limited powers over approved drugs, authorizing the agency to require manufacturers to develop and implement REMS for drugs or drug classes posing special safety risks. Components of REMS may include a lay medication guide for patients, a communication plan for physicians, and—for drugs posing the greatest risks—elements to assure safe use (ETASU), such as volume restrictions on dispensing, mandatory physician training and certification, and patient enrollment in a registry.
In September 2017, Allergan Plc announced that it had transferred the 6 patents for cyclosporine ophthalmic emulsion (Restasis), its blockbuster drug for chronic dry eye, to the Saint Regis Mohawk Tribe, a federally recognized Indian tribe of about 15 000 members in rural upstate New York with a $50 million annual budget. The Tribe received $13.75 million initially and is eligible for $15 million in annual royalties—a small fraction of the roughly $1.5 billion in annual US revenues for Restasis. The deal allows the Tribe, as the patents’ legal owner, to assert what is known as sovereign immunity in a proceeding at the US Patent and Trademark Office (USPTO) where Mylan Pharmaceuticals, a generics manufacturer, is challenging the patents.
The high prices of brand-name prescription drugs are a growing source of controversy in the United States. Manufacturers of brand-name drugs can command high prices because they are protected from generic competition by two types of government-granted monopoly rights. The first are patents on the drugs that generally define the basic period of brand-name-only sales. The second is awarded at the time of US Food and Drug Administration (FDA) approval and usually defines the minimum time until a generic can be sold. The initial patents last for 20 years and may be extended to account for time spent in clinical trials and regulatory review; other laws prevent approval of other manufacturers’ versions of new drugs for about 6 to 7 years, and for new biologics for 12 years. Overall, most new drugs receive about 12 to 16 years of market exclusivity from both kinds of monopoly protection combined. We reviewed the peer-reviewed medical and health policy literature to identify studies that described the different types of patent protection and regulatory exclusivities that shield brand-name prescription drugs from competition and thus help to sustain high drug prices. We also identified potential policy reforms intended to modify exclusivity periods to address public health needs by balancing drug affordability and industry revenue. The goal of policy in this area should be to ensure that drug market exclusivity periods provide for fair return on investment but do not indefinitely block availability of lower-cost generic drugs.