The patent-based pharmaceutical innovation system in the United States is often criticized on two grounds. First, it does not incentivize the development of drugs with the greatest impact on patient or public health, instead encouraging private investment in drugs that are likely to generate the greatest revenues. Second, it leads to drug prices that patients and health care systems cannot afford.
One well-known example of the shortcomings in the current innovation model is the direct-acting antiviral Solvadi, a drug approved by the FDA in 2013 that cures chronic hepatitis C virus infection. Payers like Medicaid were unable to offer it to all qualifying patients because of the drug’s high cost. Although prices of direct-acting antivirals have declined in recent years due to competition, they remain high, with many patients still unable to access treatment.
A new study by researchers at PORTAL takes a closer look at new, transformative models for promoting drug innovation and access. Specifically, the study analyzes three different models: delinkage, public manufacturing, and public private partnerships. All three models offer greater innovation, transparency, efficiency, and affordability.
Delinkage. Delinkage models involve payments for drug innovation based on public health value rather than patient use. Instead of rewarding innovators with market exclusivity, innovators are rewarded directly with so-called “innovation inducement prizes” or “market entry rewards.” Delinkage systems reduce or eliminate an innovator’s reliance on sales to recuperate research and development investments and earn profits. The study found that although delinkage has been proposed as a strategy to tackle antimicrobial resistance, to date there has been no large-scale implementation of delinkage models for drug development.
Public Manufacturing. Public manufacturing refers to the development and production of drugs by a government or nonprofit entity. The most prominent example is Civica Rx, which launched in September 2018 as a nonprofit devoted to bringing stability to the hospital supply chain by manufacturing common generic drugs. In addition, the Affordable Drug Manufacturing Act, first proposed by Senator Elizabeth Warren in 2018 and re-introduced in January 2020, is a proposal for a government authority to manufacture generic drugs. The study recommends that in order to protect against industry capture, governance of public manufacturing entities must be designed with clear objectives, transparency, and public participation in mind.
Public Private Partnership. Finally, public private partnerships involve publicly-funded organizations working closely with for-profit partners on drug development. The leading example is the Biomedical Advanced Research and Development Authority, a federal body created in 2006 to prepare society with biodefense and pandemic tools. Although some partnerships, such as the Drugs for Neglected Diseases Initiative, have been successful in developing and commercializing novel treatments, most partnerships continue to operate within the existing system that allows companies to retain patent-based monopolies, which can lead to high prices and suboptimal access. The study suggests that reforms related to intellectual property rights associated with such partnerships are necessary to prevent this outcome.
Each of these models exhibits promise in promoting prescription drug innovation and access. The study recommends further research to better understand these three models, with the goal of eventually creating an alternative system to the current patent-based model of drug development.
Beatrice Brown, Ben Rome
This article was originally published on Bill of Health, the blog of the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School, and was modified slightly to reflect the study authors’ affiliation with PORTAL.
Prescription drug spending in the U.S. remains high and continues to rise, accounting for about 20% of national health expenditures. While generic competition is crucial for reducing drug prices, brand-name drug manufacturers can utilize several strategies to delay such competition by increasing the length of market exclusivity for their drugs.
Although brand-name drugs only account for 18% of all prescriptions filled, they comprise 78% of total drug spending. By contrast, equally-effective, interchangeable generic drugs can offer discounts of up to 80% off their brand-name drug counterparts.
Generic competitors can only be introduced after brand-name drugs have completed their period of market exclusivity, which typically lasts 12-16 years and is largely determined by the patents covering the drug. Brand-name pharmaceutical manufacturers have strong financial incentives to prolong this market exclusivity period and delay entry of generic products.
One commonly employed approach is for a brand-name manufacturer to obtain multiple patents—some issued after the original drug goes on the market—that protect different features of the same drug, such as how the drug is used, alternate chemical formulations, or delivery devices. This creates a thicket of intellectual property protections that generic manufacturers must challenge in court for their product to reach the market. These cases are often protracted and costly for generic manufacturers, but can also result in settlements, including some in which the brand-name manufacturer pays the generic manufacturer in cash or other deals to stave off generic entry (known commonly as “pay-for-delay” settlements).
In some cases, drug manufacturers introduce a slightly different version of their drug (like a long-acting formulation) with even more patent protections. Manufacturers then vigorously encourage physicians and patients to switch to the new version as time nears for generic entry of the original version, a strategy known as “product hopping.”
These strategies to delay generic competition have substantial consequences for patient out-of-pocket prescription drug costs and total prescription drug spending in the U.S. A recent study in Health Affairs by PORTAL authors Chintan Dave, Michael Sinha, Read Beall, and Aaron Kesselheim found that Medicaid (which represents 10% of all US drug spending) spent an estimated $761 million over seven years on 31 drugs for which generic entry was delayed.
Perhaps more startling is how much the delay in generic competition for a single drug can cost the entire health system. In the case of glatiramer acetate, a commonly-used treatment for multiple sclerosis, the drug’s manufacturer effectively extended exclusivity of the brand-name drug by 2.5 years by introducing a new formulation with a different dosing regimen just before generic competition was supposed to begin. A new study in JAMA Internal Medicine by PORTAL authors Benjamin Rome, Frazer Tessema, and Aaron Kesselheim found that this “product hop” resulted in $4.3 to $6.5 billion in excess U.S. health care spending since 2015.
As prescription drug spending continues to rise and concerns about patient affordability grow, ensuring that brand-name drugs face timely generic competition is essential to maintaining fair access to drugs at reasonable prices. Doing so will require policy changes that prevent manufacturers from unreasonably extending market exclusivity for their products while still encouraging incremental improvements to existing drugs that can improve patient care. So, what can be done?
The most obvious solutions involve re-examining the system that allows drug manufacturers to obtain numerous different patents on their drugs. This can be done a few different ways.
We know that many later-issued patents used to create thickets around prescription drugs end up being overturned in court (when there is no settlement). The U.S. Patent and Trademark Office, which reviews and approves patents, could reconsider its standards for issuing drug patents. An administrative procedure to review patents called inter partes review was created in 2011 to facilitate re-examination of patents after they have been issued. Firmer patent standards would make sure that new patents protect true innovations.
Another proposal would be to restrict drug manufacturers to only a single patent against generic entrants. This “one patent, one drug” option would still allow drug developers a monopoly period—during which they can recoup their research investments—but would prevent them from gaining additional patents to extend exclusivity once the drug is already on the market.
Delays in generic competition carry a sizeable financial burden for both patients and the health care system. This burden falls disproportionately upon certain patients who require high-cost, brand-name drugs. When generic competition is delayed, these drug prices remain high and access is restricted to only the patients who can afford them.
As a result, delayed generic competition can deepen already-existing health disparities. For example, mortality from opioid use disorder is associated with markers of lower socioeconomic status. Yet the manufacturer of Suboxone—a critical yet underused medication to treat opioid use disorder—delayed generic competition by heavily promoting a dissolvable film version over the original dissolvable tablet.
This move limited access to generic versions of the drug from 2013 until 2018, and Suboxone’s manufacturer recently agreed to a $1.4 billion settlement after the U.S. Justice Department filed charges that they had fraudulently promoted the film version as safer and less prone to abuse than the tablet version. This promotion led to continued use of the high-cost brand-name drug, and high costs may have contributed to underuse and non-adherence to this life-saving medication, particularly among socioeconomically-disadvantaged patients.
Timely generic competition will ensure fairer and more equitable access to prescription drugs at reasonable prices and that the benefits and burdens of innovation will be more fairly distributed without unduly harming certain patient populations.
Generic drugs have saved the U.S. health care system $1.6 trillion dollars over the last decade. However, to ensure these savings continue, generic drugs must be allowed to enter the market in a timely fashion, and current policies afford brand-name manufacturers a number of tools to undermine generic competition and sustain their monopoly periods.
Delays in generic competition are currently costing billions of dollars, harming patients, and increasing disparities and inequities in access to care. Changing patent policy to prevent manufacturers from using these strategies represents an important yet overlooked strategy to reverse rising drug prices and ameliorate the associated economic, clinical, and ethical ramifications.
Regulatory approval characteristics of antimicrobial versus non-antimicrobial products, 1984–2018: an evaluation of Food and Drug Administration flexibilities
Jonathan J. Darrow
A looming antimicrobial resistance crisis and perceived inadequacies in the antimicrobial drug pipeline have led some commentators to recommend that the FDA relax its approval requirements. However, a number of programs already exist that provide the FDA and drug developers with substantial flexibility in the development and approval of new medicines, including the Orphan Drug Act program, the Fast-Track program, the Accelerated Approval program, the Breakthrough Therapy program, and the Priority Review program.
A new study from researchers at PORTAL traces trends in the FDA approval of new antimicrobial products, as well as how expedited regulatory approval programs have been applied to them, over the last 35 years.
This study in The Lancet Infectious Diseases found that antimicrobial drugs used at least one of these programs at least as frequently as non-antimicrobial drugs (61% vs. 53%). Antimicrobial drugs used the Priority, Fast-Track, and Accelerated Approval programs with greater frequency than non-antimicrobial products, the Orphan Drug Act program with lesser frequency, and the Breakthrough Therapy program with similar frequency. Another special program called the Animal Rule allows approval on the basis of animal studies when human trials are not ethical or feasible. Of the 14 indications approved under the animal rule, nine (64%) addressed infectious disease-related conditions.
The FDA’s flexible approach to antimicrobial products was reflected in shorter total clinical development and FDA review times, on average, compared to non-antimicrobials (5.9 vs. 7.6 years). The antibacterial subcategory had similar average clinical development times as other antimicrobial products, but substantially longer FDA review times. Antibacterials also used each special FDA program less frequently than other antimicrobials, but this is likely due to the fact that the antibacterial category was already mature in the 1980s and that these new products were not able to show any advantage over existing products, a requirements for these expedited approval programs.
Overall, this study demonstrates that the FDA is applying flexibilities to antimicrobials as appropriate, despite concerns over a lack of flexibility by some commentators.
This article was originally published on Bill of Health, the blog of the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School, and was modified slightly to reflect the study authors’ affiliation with PORTAL.
The COVID-19 pandemic has prompted several states to take steps to temporarily authorize therapeutic substitution of drugs experiencing sudden shortages, whether due to spikes in demand or supply chain disruptions.
Although these instances of replacing patients’ typical prescription drugs with different drugs intended to have the same therapeutic effects have been prompted by necessity, therapeutic substitution more generally might reduce drug spending in the United States.
In a recent piece in the BMJ by PORTAL, Jonathan Darrow, Jessica Chong, and Aaron Kesselheim explore using state laws to expand the authority of pharmacists to substitute clinically similar alternatives in order to help cut spending. Actions taken by states to temporarily allow therapeutic substitution can help them gain experience with this strategy and potentially lead to broader and more permanent drug substitution policies that could help decrease drug spending.
Some state pharmacy boards issued emergency guidance during the pandemic to allow therapeutic substitutions in the event of drug shortages.
In Vermont, for instance, the state board of pharmacy issued guidance on March 30, 2020 that temporarily authorized pharmacists to make a substitution within the same therapeutic class if it would, “in the clinical judgment of the pharmacist, have substantially equivalent therapeutic effect even though it is not a therapeutic equivalent.” The guidance requires that the pharmacist receive the informed consent of the patient, but the pharmacist does not have to notify the prescriber until after the drug is dispensed, which simplifies logistics when medicines are dispensed after-hours or whenever prescribers cannot quickly be reached. The pharmacist must notify the prescriber “as soon as reasonably possible.”
In other states, legislatures have authorized pharmacists to engage in therapeutic interchange during the pandemic. For example, in Minnesota, the state legislature enacted a provision to allow pharmacists to “dispense a therapeutically equivalent and interchangeable prescribed drug or biological product” subject to several conditions, including: the drug is in short supply and cannot be obtained from the manufacturer, drug wholesalers, or other local pharmacies; the pharmacist cannot contact the prescriber within a reasonable amount of time for authorization; the pharmacist informs the patient; and the pharmacist informs the prescriber as soon as possible of the therapeutic interchange.
In yet other states, governors’ executive orders provided for flexibility in therapeutic substitution policies. For example, in Section 33 of her Proclamation of Disaster Emergency, the governor of Iowa temporarily suspended any requirements that prevented pharmacists from engaging in therapeutic substitution without the prescriber’s prior consent. She also directed the state’s board of pharmacy to issue additional guidance.
As states face rising costs and potential shortages, they should look to state pharmacy boards or other state health agencies for guidance regarding the acceptability of various types of drug substitutions, as noted by the BMJ authors. Unlike legislators, these agencies have greater expertise regarding clinical interchangeability.
Additionally, states should monitor any changes in drug spending due to these therapeutic substitutions during the pandemic to ascertain the potential impact of a more permanent policy change, and also to avoid pitfalls. For example, states should be aware that substitution can sometimes lead to higher expenditures, such as when an expensive name-brand drug is substituted for an inexpensive generic. Because shortages occur at higher rates among less costly generic drugs, permanent substitution policies applicable during times of plenty are more likely to save money than emergency measures taken during times of shortage, when costs might actually increase.
State policymakers should be aware of the differing effects of substitution policies on drug spending during times of emergency compared to times of normalcy to best understand how data on drug expenditures from these temporary measures can inform long-term policy changes. States must also monitor the impact on patients who have been affected by substitution. This monitoring can be accomplished by adverse event reports—which are already received by the FDA—and the establishment of a specific complaint line for therapeutic substitutions during the pandemic.
If no evidence emerges suggesting a reason for concern, this may help allay fears that differences in ingredients or quality could lead to adverse effects or a decrease in efficacy. Assuaging such fears through evidence is crucial to garnering support for more permanent changes to state laws on drug substitution.
Amid tragedy, a positive outcome of the pandemic may be the demonstration via emergency measures that state governments can be flexible in substitution policies and that they can safely and effectively rely on state pharmacy boards to address health needs by broadening pharmacist authority. By closely monitoring the effect of substitutions during this time, more permanent changes to drug substitution laws might follow, which can reduce drug spending in the U.S.
Deborah Plana, Andrea Arfè, Michael S. Sinha
This article was originally published on the Health Affairs Blog.
The COVID-19 pandemic has rapidly transformed much of the medical device, pharmaceutical, and vaccine industries. As Mary McDermott and Anne Newman note in JAMA, “Mitigation efforts [against COVID-19] interfere with all aspects of a successful clinical trial: efficient accrual and randomization, intervention adherence and delivery, and outcome collection.” Quarantine, isolation, and social distancing necessarily limit access to health care institutions for care. Shortages of medical resources and staff are also possible. As a result, many non-COVID-19 trials are being suspended or terminated. Large pharmaceutical manufacturers Eli Lilly, Merck, Pfizer, and Bristol-Myers Squibb have all announced delays in enrollment for ongoing studies and initiation of future studies. According to BioPharmaDive, as of May 15, 2020, nearly 100 companies and 240 trials have experienced disruptions. As such, the COVID-19 pandemic threatens to set back non-COVID-19 clinical trial research by several years.
On March 18, 2020, the Food and Drug Administration (FDA) published “FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency: Guidance for Industry, Investigators, and Institutional Review Boards.” Updated June 3, 2020, the document focuses on logistical considerations for clinical trial conduct in the setting of COVID-19, including impact on clinical sites, clinical investigators, and trial participants. Similar documents have been published by medical societies (for example, in oncology, radiology, cardiology, and neurology), and academic as well as industry statisticians, which attempt to convey practical advice for ensuring the “rights, safety and wellbeing” of participants while mitigating risks to trial integrity. Although such documents address critical concerns, the need to salvage whatever information can still be obtained from trials during this crisis is also of pressing importance. In particular, more clarity is needed with regard to statistical considerations in ongoing, suspended, or terminated clinical trials.
In addition, existing research efforts are largely being set aside in favor of a new, urgent goal: testing, treating, and preventing the disease caused by the novel SARS-CoV-2 coronavirus. This industrywide push toward solutions for COVID-19 resulted in a pivot away from existing lines of clinical research, which creates uncertainty as to how to proceed with future clinical trials. The FDA’s shift in focus toward COVID-19 vaccines and therapeutics—as evidenced by the transition of Center for Drug Evaluation and Research Director Janet Woodcock, MD, to COVID-19 vaccine development—compounds these concerns.
To address these issues, we discuss ideas on how to maximize the amount of data generated from existing trials, ensure participant safety, and increase the feasibility of clinical studies in times of crisis.
Participants must be central to any decision to adjust ongoing clinical trials due to COVID-19. Below, we highlight some salient and generalizable considerations for individuals participating in clinical trials.
Any change that materially alters the nature of the trial must be addressed by protocol amendments. Given time constraints, amendments to multicenter clinical trials may be most expediently reviewed by a central committee rather than individual Institutional Review Boards. The COVID-19 pandemic has materially altered the risk-benefit assessment that allows for informed participation in clinical trials: an increased risk of SARS-CoV-2 exposure in health care settings without change in potential benefit. This dramatic change must be accounted for through re-consent of all trial participants. Decisions to unblind trials and offer early termination for participants in specific arms of a study or to individual participants who are especially vulnerable to COVID-19 may be warranted. This may be particularly relevant for participants in placebo or standard of care arms of clinical trials, given the relative lack of potential benefit. FDA officials have suggested in the past that use of external controls may have merit when the use of internal control arms is considered unethical. In any case, results should be returned to participants as they become available.
Other participant considerations during the conduct of the trial are also relevant. First of all, it is critical to limit in-person health status monitoring, such as blood tests and imaging, as much as possible. This is especially important for a participant in a high-risk group (such as an elderly oncology participant) or a participant who has to travel to receive care or be accompanied by others (such as children accompanied by a guardian, in which one must balance between care for the participant and risk of infecting others). Where monitoring must be done, participants should be evaluated outside the hospital or clinic setting where possible. Finally, in a slumping economy, attention must also be paid to whether enrollee compensation is ethical. Loss of health insurance or diminished income may coerce participants to remain enrolled in clinical trials, even as risks of leaving the home become more pronounced due to COVID-19. In all cases, the principle of “primum non nocere” (first, do no harm) must be the foremost concern.
Issues Related To Ongoing Trials: The Role Of Data Safety Monitoring Boards
Both the FDA Guidance and other similar documents recognize that many clinical trials may need to interrupt patient enrollment due to the impact of COVID-19. However, they offer little guidance on which statistical criteria could guide the decision to suspend trial activities, and whether and how to still analyze the data collected on experimental therapies.
In some cases, the Data Safety Monitoring Board could potentially perform an ad-hoc interim analysis based on formal stopping rules. For trials that collected most study outcomes, interim analyses could determine that the primary objective has been reached before the planned end of study. Futility stopping rules could instead help identify trials likely to fail even if continued. Both approaches could help minimize the number of patients that need to be enrolled in a trial during a crisis.
Nevertheless, more guidance is needed on when similar analyses could be appropriate. Two issues should be considered before performing interim analyses for early stopping, especially if unplanned. The first concern is the need to control the false-positive error rate (the probability that a trial would incorrectly produce positive results by chance) at a low, pre-specified level. This risk of false-positive findings is increased when assessing the same hypothesis multiple times, as would be the case in interim analysis. False-positive error rates could be controlled at pre-specified levels using multiple testing methods such as group sequential approaches. The second concern is ensuring the reproducibility of study results. To overcome this potential limitation, any unplanned analysis and decision rule for early stopping should be documented in amendments to the study protocol.
Optimizing Use Of Existing Data And Results: The Importance Of Dissemination
Many trials are likely to shut down during the current pandemic, but this should not translate into a loss of useful data. First, meta-analyses and methods to adjust for missing data, such as multiple imputation methods, can leverage data from discontinued trials to provide important information on the safety and effectiveness of tested therapies. Second, some protocol deviations due to COVID-19 may be unavoidable, which may increase the risk of bias in study results. Robustness of study findings could be evaluated in re-analyses of shared data based on different bias assumptions. Finally, the FDA should promote sharing of anonymous participant data and summary results from trials affected by the pandemic, even those terminated before their final analyses. More generally, it should enforce and expedite the reporting of study results. Even though the Food and Drug Administration Amendments Act requires timely reporting of results of applicable clinical trials to ClinicalTrials.gov, only 13 percent of trials post their results on this site within 12 months of trial completion.
Making the most out of data collected from trials during the current pandemic requires making such information widely available for re-analysis as quickly as possible without compromising participant safety and privacy. Notably, such calls for the widespread implementation of data sharing have been raised with regard to pediatric trials and rare diseases, which outside of a pandemic already face considerable challenges in enrolling limited numbers of participants in trials. In the context of a public health crisis, such populations are even more likely to be vulnerable to accrual problems, discontinuation, and nonpublication of study results.
Decentralization: A Future For Clinical Trials?
The current pandemic highlights a glaring inequity in the way that clinical trials have historically been conducted in the US: They are mostly performed in a few central locations, typically key urban centers. Given the disproportionate effects of COVID-19 on densely populated urban areas, it is expected that non-COVID-19 clinical trials conducted in such locations will struggle with enrollment and monitoring.
In contrast to traditional clinical trials, decentralized clinical trials are “trials executed through telemedicine and mobile/local healthcare providers,” as defined by the Clinical Trials Transformation Initiative. Prior to the pandemic, it had been widely reported that a lack of geographically diverse clinical trial sites negatively impacts study participation, especially for the enrollment of women, as well as participants from rural areas and racial groups traditionally underrepresented in biomedicine. On the contrary, decentralized trials may help increase trial access and participant diversity.
The COVID-19 pandemic highlights an additional advantage for study decentralization: increased robustness of participant accrual in the face of a crisis. Indeed, decentralized trials could ensure continued accrual and monitoring of participants even when in-person care is no longer possible in some study locations. Still, the technical requirements for performing decentralized trials, such as remote monitoring, can make them infeasible for some therapy and disease settings with currently available technology.
Society should invest in the innovation required for widespread adoption of decentralized trials. Such innovation would promote distributive justice, ensuring that all populations affected by a disease have the opportunity to participate in—and reap the benefits of—clinical trials. Investment in technologies to help decentralize clinical trials would additionally increase the resilience of our country’s clinical research programs in the face of large-scale emergencies.
Aaron S. Kesselheim
Welcome to the PORTAL Blog!
The goal of this blog will be to provide some deeper insights into PORTAL’s work, as well as reflections from the PORTAL team and our colleagues on the discovery, development, approval, availability, and evidence-based use of prescription drugs (and other health care products).
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PORTAL Blog posts are authored by PORTAL faculty, trainees, and collaborators.