Changwon C. Lee
Biologic drugs are among the most expensive prescription drugs in the US, accounting for nearly 40% of all prescription drug spending. In 2010, Congress passed the Biologics Price Competition and Innovation Act (BPCIA) to create an abbreviated regulatory approval pathway for biosimilars, which are products that show high similarity to “originator” biologics and exhibit no clinically meaningful differences in safety, purity, and potency. By reducing the time and cost of biosimilar entry, the BPCIA intended to promote competition and curb spending. To date, however, the success of the BPCIA pathway has been limited, and only a small number biosimilars are currently available in the US.
A new study by researchers at PORTAL, published in Mayo Clinic Proceedings, estimated the development times of US biosimilars under the BPCIA. Using a commercial pharmaceutical pipelines database, the authors identified 40 biosimilars that initiated phase I or I/II testing in the US between 2012 and 2015 and recorded their trial lengths and phases. The study found that nearly all forty biosimilars underwent phase III testing with an average trial length of 22 months. For 20 biosimilars that had been approved by October 2019, the median time from initiation of phase I testing to approval was 69.9 months.
The BPCIA pathway was intended to accelerate biosimilar approvals, yet in the first 3 years of its implementation, most biosimilars underwent phase III testing and took almost 2 years to complete. Such levels of extensive testing likely contributed to limited biosimilar market entry, limiting price reductions.
There may be opportunities for improving the efficiency of pre-approval testing for biosimilars. The FDA has already made important strides in this regard. If further efficiency isn’t feasible, subsidies for pre-approval biosimilar clinical testing may be warranted to ensure sufficient market entrants and thus improve patient access to affordable biotherapeutics.
Heterogeneity of antidiabetic treatment effect on the risk of major adverse cardiovascular events in type 2 diabetes
A major barrier to effective implementation of favorable findings from trials on anti-diabetic treatments – such as glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose cotransporter-2 inhibitors (SGLT-2i) – into clinical practice is the scarcity of evidence describing the extent to which these results may be generalizable to all patients with type 2 diabetes or whether they may vary across subgroups of the population.
Such variation in therapeutic outcome is called “treatment effect heterogeneity.” Identifying treatment effect heterogeneity in a trial population is necessary to individualize treatment and target the groups of patients that optimally benefit from a specific therapeutic strategy in clinical practice. However, subgroup analyses within a single trial are not usually powered to detect treatment effect heterogeneity.
A new study from PORTAL published in Cardiovascular Diabetology explored whether diverse subgroups of patients with type 2 diabetes (enrolled in clinical trials) appear to have different rates of major cardiovascular events to two important new categories of anti-diabetic drugs: SGLT-2is and GLP-1 RAs. The identification of subgroups of interest emerged from baseline characteristics of the trial population, which have been deemed a priori as potential treatment effect modifiers in trials investigating the association between SGLT-2i or GLP-1 RA drugs and major cardiovascular events.
The authors conducted an exploratory meta-analysis of placebo-controlled randomized trials that investigated products within the SGLT-2i and GLP-1 RA drug classes in participants with type 2 diabetes. The trials need to report major adverse cardiovascular events as a primary outcome, follow-up patients for longer than 6 months, and describe phase 3 trial dosage. The potential modifiers were baseline factors of the trial populations measured at randomization and were classified in four groups: cardiovascular factors (established atherosclerotic cardiovascular disease and heart failure), renal function (estimated glomerular filtration rate, as indicator of chronic kidney disease), cardiometabolic factors (HbA1c, duration of diabetes, BMI and systolic and diastolic blood pressure) and demographic factors (age, gender, race). All potential effect modifiers considered were part of the pre-specified subgroup analyses of the included trials. Ten trials enrolling 89,790 patients were included in the analyses.
The average benefits of SGLT2i or GLP1-RA drugs considering all patients enrolled in the trials, regardless of their different baseline characteristics, resulted in a 11-12% risk reduction of major adverse cardiovascular events. However, subgroup meta-analyses showed a 14% risk reduction of major cardiovascular events in patients with established cardiovascular disease [GLP1-RA: 0.86 (95% CI, 0.80-0.93); SGLT-2i: 0.86 (0.80-0.93)], and no effect in at-risk patients without history of cardiovascular events [GLP1-RA: 0.94 (0.82-1.07); SGLT-2i: 1.00 (0.87-1.16)]. A trend toward larger treatment benefits was observed with SGLT-2i among patients with chronic kidney disease [0.82 (0.69-0.97)], and patients with uncontrolled diabetes for both GLP1-RA or SGLT-2i [GLP1-RA: 0.82 (0.71-0.95); SGLT-2i: 0.84 (0.75-0.95)]. Uncontrolled hypertension, obesity, gender, age and race did not appear to modify the effect of these drugs.
Among several clinically important patient characteristics measured before treatment initiation, history of established atherosclerotic cardiovascular disease appears to be the only modifier of the treatment effect of SGLT2i or GLP1-RA drugs with respect to major cardiovascular events. We observed signals toward larger benefits among patients with baseline chronic kidney disease for the SGLT-2i treatment, and among patients with baseline uncontrolled diabetes for both SGLT-2i or GLP1-RA drugs. Presence of chronic kidney disease and uncontrolled diabetes should be further investigated as potential effect modifiers of the association between SGLT2i or GLP1-RA drugs and major cardiovascular events.
Last Friday, September 11th, PORTAL hosted the first event in its annual series of Health Policy and Bioethics Consortia, “COVID-19, Public Health Ethics and Policy for Pandemics.” The consortia aim to define and stimulate discussion of key issues in healthcare and public health that raise ethical questions and policy responses, and the series brings together experts with different perspectives to consider the problems and solutions.
Since the SARS-CoV-2 pandemic began, a wide range of policy and ethics issues have arisen; the consortium focused on the challenge of making policy decisions when there is uncertainty about the pandemic and moral uncertainty about what policies and actions are right to take.
Presenting first was Marc Lipsitch, DPhil, Professor of Epidemiology and Director of the Center for Communicable Disease Dynamics at the Harvard T.H. Chan School of Public Health. As a well-known researcher in the field of infectious disease dynamics, Dr. Lipsitch explained some of the basics of modeling a situation like the SARS-CoV-2 pandemic and how the available data is rarely sufficient to draw conclusions with high certainty. The value of the models can be to reveal the extent of uncertainty and assist decision-makers to understand the risks of different policy options, including doing nothing. In his talk, he demonstrated how modeling can provide a useful resource when decisions need to be made quickly, and, using the example of a 2002 smallpox vaccination campaign in the US, that the information must be frequently re-assessed to determine if the policy needs to change.
Next, Matthew Wynia, MD, MPH, Director of the Center for Bioethics and Humanities at the University of Colorado Anschutz Medical Campus, delved into the ethics of the COVID-19 response and attitudes towards infectious disease. He structured his presentation around “the three R’s of ethics in epidemics”: restrictions on liberty, resource allocation, and responsibilities. Dr. Wynia discussed the history of blame and stigmatization of infectious diseases before turning to the current situation. He also emphasized the need for frequent re-assessment of decisions since initial decisions, like ventilator allocations, should be revised to the immediate situation. Polling the audience, he highlighted the kinds of ethical problems and disagreement that arise, even when unpacking simple sounding principles like “save the most lives.” He concluded by discussing the evidence for quarantine and the challenges of imposing restrictions on liberty, pointing to experiences from the SARS epidemic when some quarantine attempts backfired.
The two speakers then took audience questions, engaging in a discussion about how to present complicated and changing information to the public, promote public trust in and the trustworthiness of institutions, and address pre-existing inequities in new public health decisions. As Dr. Lipsitch noted, good decision-making early on in the pandemic could preclude some ethical challenges later in it; but some of these challenges, as noted by Dr. Wynia, arise from balancing between the ethical principles that should guide any response.
A recording of the session will be available soon.
Prescription drug prices in the US far exceed those of other countries given that manufacturers set prices at their own discretion. This is in contrast to the UK where prescription drugs are paid for by the National Health Service (NHS), which in turns plays a central role in negotiating the prices of brand-name drugs. For example, the Voluntary Scheme for Branded Medicines Pricing and Access places limits on NHS spending growth and profits that manufactures can earn on brand-name drugs.
Recent political changes may affect how drugs are priced in the UK. The US and UK governments intend to form a bilateral trade agreement after the UK left the European Union on January 31 via Brexit. Pharmaceutical drug prices will likely be a central component of trade negotiations since the Trump Administration has ordered the US Trade Representative to combat global use of drug cost-containment measures. In fact, a recent summary of specific negotiating objectives published by the US Trade Representative reveals that it is pursuing “full market access” for US pharmaceuticals and medical devices in the UK. The US has successfully negotiated more industry involvement in drug pricing and elimination of cost-containment measures in past international trade agreements.
Our new study, by PORTAL researchers in collaboration with researchers at the University of Oxford, aimed to provide context around the potential US-UK trade deal and estimate the cost impact of a scenario in which UK brand-name drug prices change to match those of the US. Using monthly prescribing data files from NHS England, the authors identified the costs and volume prescribed for all drugs in English primary care in 2018. The NHS spent £1.39 billion (~$1.8 billion) on 50 single-source brand-name drugs with the highest expenditure in English primary care. The authors conducted comparative cost analyses and projections using prices from Medicare Part D in the US. All drug prices in the US were more expensive than those of the UK, even after accounting for estimated US rebates. The US-English price ratios ranged from 1.3 to 9.9, with a mean ratio of 4.8. After accounting for price and volume, if NHS England paid US prices in 2018, then overall spending on the 50 single-source brand-name drugs would have been 4.6 times higher: an increase of £5.03 billion (~$6.6 billion). The projected spending increase on this cohort of 50 drugs represents 63% of all 2018 English primary care drug spending.
Beatrice Brown, Neeraj Patel
Assessment of Variation in State Regulation of Generic Drug and Interchangeable Biologic Substitutions
Chana A. Sacks, Ameet Sarpatwari
High prescription drug spending remains a major issue, as pharmaceutical manufacturers continue to mark up the prices of products during the COVID-19 pandemic. Brand-name drugs are the primary driver of this spending, with the prices of brand-name biologic drugs in particular having risen dramatically in recent years. When generic drugs become available, they can substantially lower drug prices, and policymakers hope that follow-on biologic drugs can eventually generate similar competition.
Generic drugs are so effective at lowering drug prices because of state “drug product selection laws” that allow pharmacists to automatically fill prescriptions for brand-name drugs with generics and prescriptions for biologic drugs with FDA-designated interchangeable follow-on biologics. In a new study in JAMA Internal Medicine, we reviewed the current landscape of drug product selection laws in the US, including how different states approach interchangeable biologic substitution. We found considerable variation in these laws. For small-molecule drugs, 31 states did not mandate generic substitution by pharmacists (but merely made it “permitted”), 7 states required patient consent prior to generic substitution, 32 required special notification by the pharmacist, and 24 states did not explicitly protect pharmacists from liability related to making the substitution. Compiling a generic substitution score, in which a maximum of 1 point was assigned for each of the four exposure variables—with higher points indicating regulatory requirements limiting substitution—we found that 9 states had scores of 3 or higher. In the case of biologic drugs, 45 states had heightened requirements related to substitution of interchangeable follow-on biologics, most commonly requiring mandatory notification of the prescribing physician.
Overall, this study demonstrates considerable scope for states to optimize their drug product selection laws to achieve more efficient substitution of FDA-approved generics and interchangeable biosimilars. These changes would lead to greater reductions in spending and improvements in patient adherence.
On August 30, FDA Commissioner Stephen Hahn remarked that the FDA is willing to issue an Emergency Use Authorization (EUA) for a vaccine before the completion of Phase III clinical trials, if the benefits outweigh the risks. EUA authority is granted by the Federal Food, Drug, and Cosmetic Act, allowing the FDA to make unapproved products or unapproved uses of an approved product available during a public health emergency in the absence of a suitable, approved alternative.
EUAs have been issued for several drugs and products during the pandemic, including convalescent plasma just last week, remdesivir, and hydroxychloroquine (which has since been revoked). However, unlike drugs that are intended to treat unhealthy patients, vaccines are intended to be deployed to millions of healthy citizens, making safety and efficacy even more paramount. But a rushed EUA can undermine both this safety and efficacy.
In a recent Viewpoint in JAMA, PORTAL researchers argue that premature rollout of a vaccine from unprecedented political and economic pressures could result in a major public health misstep. The authors explain the various mechanisms that FDA can utilize to expedite access to a vaccine, but they question whether expedited pathways—particularly, the issuance of an EUA—can negatively impact safety and efficacy by undermining randomized trials and public health measures like social distancing, as well as by missing opportunities for learning about the vaccine’s safety early on. Furthermore, current vaccine hesitancy not only makes it less likely that we will attain needed herd immunity, but it also means that any safety and efficacy issues with an expedited vaccine can undermine the public’s already fragile trust in vaccines. In the midst of one of the worst pandemics in recent history, science and data should come before politics and economics—the FDA can ensure the safety and health of the American public by acting on this data and not succumbing to political and economic pressures.
Liam Bendicksen, Jonathan J. Darrow, and Aaron S. Kesselheim
This article was originally published on the Health Affairs Blog.
Tackling prescription drug costs remains a top priority for voters. Drug spending in the US is driven both by increasing overall prescription volumes and by high prices for brand-name drugs, which are set freely by manufacturers during patent-protected exclusivity periods that last about 13.5 years after drug approval, on average.
One important means of addressing the price component of rising expenditures is to facilitate the market entry of generic drugs after exclusivity periods for brand-name drugs last a reasonable amount of time, since the availability of substitutable generics often leads to rapid and substantial reductions in payer drug spending and patient cost sharing. The latest proposal to encourage timely generic entry is a bill in Congress intended to help efficiently screen out improperly issued drug patents.
The Problem: Delays In Generic Entry Caused By Improperly Issued Brand-Name Drug Patents
Improperly issued drug patents can and do delay the entry of generic drugs. Indeed, a key strategy of brand-name pharmaceutical manufacturers is to obtain patents not just for active ingredients, but also for peripheral features such as a drug’s coating, formulation, or delivery mechanism. In a previous study, we showed that two highly profitable active ingredients were covered by scores of patents. In some cases, these patents may be obtained after FDA approval of the original drug product (though usually based on patent applications filed prior to drug approval) and extend many years in the future at the time the patent on the active ingredient expires and generics are ready to enter the market. As a result, manufacturers of generics frequently must challenge brand-name drug patents in court to sell their products in the US.
To address such improperly issued patents, the 1984 Hatch-Waxman Act created a framework that encouraged manufacturers of generic drugs to challenge brand-name patents in court. In the 1990s and 2000s, generic manufacturers prevailed in challenges of method-of-use and formulation patents between 33 percent and 71 percent of the time. But even an ultimately successful court challenge can entail a protracted legal battle that can delay timely entry of a generic, or even deter entry entirely.
Moreover, the Hatch-Waxman Act provides that when patents are listed in the FDA’s “Approved Drug Products with Therapeutic Equivalence Evaluations” (commonly known as the “Orange Book”), a lawsuit initiated within 45 days by a brand-name manufacturer triggers a 30-month stay of FDA approval of the generic product, delaying generic market entry by two-and-a-half years or until the litigation resolves, whichever occurs sooner.
The Second Look Act
The Second Look at Drug Patents Act of 2020 (The Act), cosponsored by Sens. Patty Murray (D-WA) and John Cornyn (R-TX), would increase awareness of a quicker, more efficient way to challenge brand-name patents, without costly litigation and before they are listed in the Orange Book: inter partes review, an administrative process that Congress created in 2011 as part of the Leahy-Smith America Invents Act that allows the United States Patent and Trademark Office (USPTO) to reevaluate its initial decision to grant a patent. The Second Look Act would amend the Food, Drug, and Cosmetic Act to require sponsors of new drugs to notify the USPTO after submitting patent information to the US Food and Drug Administration (FDA).
The USPTO would be required to provide notice of these patents on a new website it would create and maintain and in the USPTO’s Official Gazette, a weekly publication. These notices would help alert interested parties that they could file a petition for inter partes review.
Inter partes review can reduce the need to litigate the validity of drug patents in federal court. Compared to litigation, inter partes review has several advantages. Most importantly, it is generally cheaper, quicker, and more efficient than court-adjudicated lawsuits. The Patent Trial and Appeal Board (PTAB), which adjudicates inter partes reviews, is an expert body with more than 200 Administrative Patent Judges that collectively have greater expertise across a wide range of scientific and patent law issues than do most federal district courts.
The PTAB uses the evidentiary standard of a “preponderance of the evidence” to determine if a patent is invalid, while courts apply the higher threshold of “clear and convincing evidence” to invalidate a patent, making it easier for a patent challenger to prevail before the PTAB. Any person may initiate an inter partes review at any time, potentially long before a generic drug application is filed. Prior questions about the constitutionality of inter partes review have been resolved, and the process now appears to be on solid legal ground.
Of course, inter partes review does not guarantee invalidation of drug patents since, as with court litigation, patents will remain intact if they were validly granted. For example, only 3 percent of active ingredient patents challenged in Hatch-Waxman Act litigation were found invalid or not infringed. But early evidence suggests that inter partes reviews conducted by the PTAB are an effective way to address improperly granted patents, including drug patents. From September 2012 to November 2018, final written decisions issued by the PTAB invalidated 46 percent of claims in Orange Book-listed patents (patents often have multiple “claims” that define the scope of exclusionary rights).
The Need For Additional Action
While increasing awareness of inter partes review is important, it is crucial to recognize that the Second Look bill does not alter the existing inter partes review process for challenging patents in any way. Furthermore, the patent information provided by the Second Look Act is already in the public domain. Since 1984, federal law has required that drug patent information be provided to the FDA at the time of new drug application submission, and then listed in the Orange Book, which is freely available online. The USPTO already publishes information about new patents in its Official Gazette.
Thus, while the Second Look Act might be helpful, more could be done to help generic drugs come to market. For example, patent law currently provides that “a patent shall be presumed valid,” placing the burden on the litigant challenging the patent to prove invalidity by clear and convincing evidence. Rep. Hakeem Jeffries (D-NY) and Rep. Doug Collins (R-GA) have proposed shifting this burden of proof to the brand-name manufacturer.
Other policy alternatives include restricting the types of patents that may be listed in the Orange Book. For example, researchers have proposed that policymakers restrict Orange Book listings to a single patent per drug, or to only those patents covering the active ingredient of a drug. Lawmakers could also prohibit late-listed patents, i.e., patents not submitted to the FDA until after the filing a new drug application, unless a patent covers changes that confer additional clinical benefits. However, the listing of patents in the Orange Book was intended to increase transparency and facilitate the filing of patent challenges by generic drug companies, so listing only some patents would frustrate this goal.
A better option would be to continue to require that most patents be listed in the Orange Book, but reduce the 30-month stay to a shorter period, such as 18 months. Lawmakers could also limit the stay to a narrower set of patents or eliminate the stay entirely, though this could lead to delayed litigation (and thus delayed generic entry) by removing the incentive for brand-name manufacturers to bring patent challenges within 45 days.
Publishing drug patent information in the Official Gazette and a new USPTO website may elevate the visibility of both new drug patents and the inter partes review process, and could encourage generic manufacturers and other interested parties to challenge those patents. But its potential impact, even if enacted, is likely to be limited. Historically, approximately 91 percent of Orange Book-listed patents challenged in inter partes review have also been challenged in court, and 95 percent of Orange Book inter partes review petitions were filed after court litigation began.
These figures suggest generic manufacturers are seeking the more challenger-favorable evidentiary standards and other benefits of inter partes review to help clear a path to market entry, but may be less willing to forego the 180-day exclusivity available to first generic patent challengers under the Hatch-Waxman Act (which inter partes review does not provide).
While the Second Look Act is a step in the right direction, other ways that lawmakers can address the issue of invalid drug patents delaying generic entry will likely go further towards ensuring a proper balance between drug innovation and access.
Michael S. Sinha
Antimicrobial resistance is a very real public health concern, but existing incentives have largely failed to stimulate a robust pipeline of antibiotic development. There are two major types of incentives. "Push incentives" come in the form of early funding of research and development that helps "push" a drug through trials and toward approval. In contrast, "pull incentives" come in the form of lucrative awards for successful drug approvals, intended to "pull" manufacturers toward targeted research and development.
Most recently-proposed legislative incentives for antibiotic development largely fall into the latter category. The 21st Century Cures Act's Limited Population Pathway reduced the evidentiary threshold for antibiotic approval. The GAIN Act's Qualified Infectious Disease Product (QIDP) designation doubles the length of Hatch-Waxman exclusivity for qualifying antibiotics (from 5 to 10 years). Another program offers priority review vouchers (PRVs) for drugs to treat tropical diseases, which can be redeemed to expedite FDA review of future drug applications. Finally, wildcard vouchers have been proposed to extend patent exclusivity of marketed drugs in exchange for successful approval of a new antibiotic.
A new article by PORTAL researchers in The Journal of Infectious Diseases reviews the latest pull incentives for developing novel antibiotics, which increase reimbursement by the Centers for Medicare and Medicaid Services for inpatient use of new antibiotics. We argue that such financial incentives will—like the other pull incentives described above—continue to favor new antibiotics with limited additional value over existing therapies. We instead recommend incentives that promote the development of better therapies that advance the care of patients with resistant infections.
Preferences for and Experiences with Pill Appearance Changes: National Surveys of Patients and Pharmacists
Rachel E. Barenie
Medication nonadherence occurs when patients do not take their medications as prescribed and can be due to numerous factors, such as side effects and high drug costs. Ultimately, nonadherence is tied to poorer patient outcomes and billions of dollars in healthcare spending annually. One possible contributor to nonadherence is the lack of consistency in the appearance of a patient’s medication.
In this new study, PORTAL researchers collaborated with the US Food and Drug Administration to better understand patients’ and pharmacists’ preference for and experiences with changes in pill appearance. These included changes in the size, shape, color, and markings of medications. We conducted two independent surveys of practicing pharmacists and patients between January and April of 2016. Patients were 50 years or older and taking medications for one of six chronic diseases. We probed more about how often these changes were occurring, what their (both patients and pharmacists) responses to the changes were, and others.
The study found that most patients reported experiencing a change in their pill’s appearance and preferred to be notified about those changes. Fewer than half the patients participating in the survey, however, reported being notified either verbally or with a sticker on their prescription bottle about the change. Of patients who reported a change, 12% reported they either stopped taking or used their medication less frequently because of the change. We found that most pharmacists reported that these changes occurred frequently in their pharmacies and most reported notifying patients when a change occurred.
PORTAL Blog posts are authored by PORTAL faculty, trainees, and collaborators.