Cardiovascular therapy: More new drugs for a growing patient base

Pharmaceutical CommercePharmaceutical Commerce - July/August 2016

The scale of the cardiovascular market pushes payers to demand quality outcomes data

cardiovascular therapy

Fig. 1. Over 200 CVD drugs are in development. Credit: PhRMA[/caption]

When looked at as a unified market, cardiovascular disease (CVD) is a very large, heavily populated ecosystem, inhabited by large numbers of healthcare delivery systems, therapeutic drugs, medical devices and drug/device combinations, patient support systems and advocacy groups. All this befits CVD’s continuing status as the No. 1 killer, ending the lives of 610,000 Americans each year (and 15 million worldwide, according to WHO). The American Heart Assn. estimates that 85 million Americans (roughly one in three adults) have at least one form of CVD.

Waves of new pharmaceutical products—antihypertensives, beta blockers, ACE inhibitors, statins, beta agonists, alpha blockers, alpha agonists, sodium channel blockers, calcium channel blockers, vasodilators, renin inhibitors, angiotensin receptor blockers, diuretics and thrombolytics—have been brought to market over past decades; most of these products are now generic. But that hasn’t dampened the enthusiasm of drug developers to go after new ones; some 200 CVD drugs are in clinical trials, according to PhRMA. However, many of the latest drugs are meeting stiffening resistance among prescribers, in large part due to high cost and uncertain medical benefit.

Another issue affecting cardiovascular care is that a worrisome number of CVD drugs are in short supply. Data from FDA and the Univ. of Utah Drug Information Service (a recognized authority on this subject) indicate that one out of 10 drugs on short-supply lists during the past decade or so have been for CVD. In many cases, the drugs are first-line therapies for which there are few alternatives. FDA has had some success in reacting to the shortages, but for a therapy class as broad as CVD, the situation 
is worrisome.

Up and down costs

In terms of the drug spend associated with CVD, the 2015 Express Scripts Drug Trend Report indicates that both cholesterol and high blood pressure (and related CVD disease management) remain among the top five costliest traditional drug therapy classes, and together accounted for 25% of the total traditional drug spend in 2015. However, thanks to the increasing availability and use of generics in both categories, the US drug spend on cholesterol-lowering drugs was down by 9.2% in 2015 (compared to the prior year), while the drug spend on blood pressure and other CVD medications was down by 12.5% in 2015. Today, generics account for 83% of all anti-cholesterol medications used currently.

Express Scripts projects further decreases in the drug spend for anti-cholesterol medications of 11–14% each year during 2016, 2017 and 2018, as the last popular branded statins Crestor (rosuvastatin) from AstraZeneca, Zetia (ezetimibe) and Vytorin (ezetimibe/simvastatin) from Merck all give way to generic competitors in 2016 and 2017.

Similarly, annual spending for blood pressure and other CVD medications are projected to decrease by 4–9%/year during 2016, 2017 and 2018, in part because generic alternatives to Benicar (olmesartan medoxomil) and Benicar HCT (combined with hydrochlorothiazide), the largest-selling angiotensin receptor blocker (ARB) will become available in October 2016.

Despite the fact that several eagerly anticipated new CVD-related medications have been approved over the past year or so, many have entered the ring with more of a whimper than a bang. These high-cost branded products face a steep acceptance curve, as they enter classes that are already dominated by proven generics. The same pressures impact the market for drug-device combinations and medical devices, as well.

Nursing a broken heart

As a disease state, CVD casts a long shadow, encompassing numerous chronic and deadly disorders related to the heart and blood vessels. These include congestive heart failure, angina, arrhythmia, hypertension, coronary artery diseases, peripheral artery disease (PAD; a marker of systemic atherosclerosis), thrombosis, ischemic heart disease and stroke. Many of these conditions are related to precursor health conditions, including high blood pressure, high cholesterol, diabetes and obesity. Underpinning it all are the many lifestyle factors—unhealthy diet, lack of exercise, obesity, tobacco and alcohol use among others—that are directly or indirectly to blame.

CVD medications typically work by either enhancing the heart’s pumping capacity, increasing oxygen supply to the heart, or reducing the levels of low-density lipoprotein (LDL) cholesterol (so called “bad” cholesterol) or raising high-density lipoprotein (HDL) cholesterol (so-called “good” cholesterol).

One of the newest medicines to treat heart failure, Entresto (sacubitril/valsartan) from Novartis, which is a combination of angiotensin receptor blocker (ARB) valsartan and the neprilysin inhibitor sacubitril. It was launched in 2015, and to the surprise of many industry observers, it has been met with some resistance. “Entresto is notable for both its clinical trial results—with significant mortality benefit demonstrated—and for the cautious reception it has received in the provider community,” says Michael Kleinrock, director of research development, IMS Institute for Healthcare Informatics. “Some observers expected wider usage based on Entresto’s clinical profile, but have had to readjust their expectations based on lower usage since it first launched.”

Novartis reported first quarter 2016 US sales of $17 million, which some industry observers consider to be a slow start for a presumptive blockbuster drug. Entresto encountered such a steep uphill climb right from the starting gate in part because “the medicines it would replace are already well understood by doctors and most are available generically,” says Kleinrock. And, because “patients with heart failure typically skew toward relatively lower socio-economic status, Entresto’s high cost will always be a factor.” He notes that many prescribers anticipate that these patient demographics and high drug costs, coupled with a high drug copay and the burden of requiring a prior authorization, will reduce adherence when Entresto is prescribed. “If doctors are not sold on the clinical concept enough to risk potential cost-based non-adherence, they might be reluctant to prescribe the drug,” he adds.

Another area of general interest within CVD is the new class called novel oral anticoagulants (NOACs), which reduce blood clots to prevent thrombosis or stroke. Examples include Pradaxa (dabigatran etexilate) from Boehringer Ingelheim, Xarelto (rivaroxaban) from Janssen, and Eliquis (apixaban) from Bristol-Myers Squibb. “These drugs are steadily gaining wider adoption, replacing decades-old generic warfarin blood thinners,” says Kleinrock.

“For manufacturers of newer, high-cost CVD medications, obtaining favorable coverage and formulary position is the first step to reducing barriers to patient access. This requires collaboration and communication with payers, who are becoming increasingly concerned with real-world value and the effect a drug will have on the overall patient experience,” says Mike Eaddy, PharmD, PhD, VP of real world evidence for Xcenda, a part of AmerisourceBergen. “In the absence of real-world data upon product launch, manufacturers must follow through to develop an evidence-based strategy that leverages real-world sources of information to fill evidentiary gaps,” he adds. “This includes electronic medical records, insurance and pharmacy claims data linked with lab data, and prospectively designed observational studies to demonstrate that these products are working and providing effective clinical outcomes.”

“Medicines that treat cardiovascular-related illnesses represent an incredible new opportunity for patients, caregivers and prescribers, and long-term opportunity for payers, in terms of promoting greater health and wellness and offsetting major cardiovascular events down the line,” says Derek Cothran, VP and lead, strategic account management, Lash Group, a part of AmerisourceBergen.

However, CVD drugs now have to navigate more complex treatment protocols, due in part to their rising costs. For instance, Cothran explains, “Payers have placed strict utilization restrictions on up to 80% of initial prescriptions for some of today’s CVD medications, such as the classes for deep vein thrombosis (DVT), venous thromboembolism (VTE), congestive heart failure or the PCSK9 inhibitors (discussed below), with many of these taking more than 10 days for a determination.” Against this backdrop, many manufacturer-sponsored programs “have planned for this and recalibrated their plan offering, often providing ‘starter’ or ‘bridge’ products to patients who are in need of medicine and are unable to wait for a payer decision.”

cardiovascular therapy

Fig. 2. CVD fatality is on a downward slope.[/caption]

PCSK9 inhibitors receive a lukewarm welcome

Nowhere is this playing out more fiercely in CVD right now than within so-called PCSK9 inhibitors—the newest class of cholesterol-reducing medications that are approved for a relatively narrow subset of patients (those with severe hyperlipidemia) who are at high risk for cardiovascular disease and aren’t able to control LDL cholesterol through diet or the highest-tolerated dose of statins. Unlike the widely used pill-form statins, most of which are now in generic form, the PCSK9 inhibitors are costly, self-injectable biologic agents, which must be self-administered every two weeks or once/month, so while they have certainly been generating a lot of interest, adoption has been slow to materialize.

In mid-2015, the first of two PCSK9 inhibitors medications were approved— Repatha (evolocumab) from Amgen and Praluent (alirocumab injection) from Sanofi/Regeneron. Pfizer also has a PCSK9 inhibitor candidate (bococizumab), which is currently in Phase III clinical trials. Right from the start, these introductions were met with mixed emotion among key stakeholders. While clinical trial data for both have confirmed impressive results, each has a list price around $14,000 per year, so it takes a strong case to justify the use of PCSK9 inhibitors in the face of proven, low-cost, generic oral statins.

“The manufacturers and insurers alike have been somewhat surprised. While these drugs have been making significant gains in terms of clinical effectiveness, they have not been greeted very warmly, not just because of their high price tag, but also because the existing standards of care have so much long-term, real-word CVD event outcomes data to really validate the benefit-risk profile of the existing products,” says John Doyle, DrPH, MPH, SVP, advisory services for Quintiles. “As a stakeholder you say ‘Okay, this looks promising, but only when long-term real-world evidence becomes available for the newer agents can a true apples-to-apples comparison occur,’ and with a higher price differential, payers are saying ‘Let’s just pull back the reins a bit.’”

Last September, just as the PCSK9s entered the market, the Institute for Clinical and Economic Review, a nonprofit policy group, issued an analysis claiming that Repatha and Praluent should be priced closer to $2,200 per year based on their value relative to generics. Both Amgen and Sanofi/Regeneron are in the process of gathering real-world evidence to verify that the favorable clinical trial results can be sustained under messy real-world conditions, but the earliest of these results are not expected until 2017. Despite ICER’s assertions, both Amgen and Sanofi/Regeneron have stood by their pricing policy, citing the significant unmet need for patients who would be best served by these medications and the long-term clinical outcomes and savings potential they promise.

“The expectation is that once the real-world data confirms—or raises questions—about the clinical trial results, payers and providers will be able to adapt their understanding of appropriate use,” says Kleinrock of IMS Institute. “Are they worth the cost multiplier for more patients? Only time 
will tell.”

Nor should it be overlooked that while the PCSK9-generic comparative effectiveness is being evaluated, the manufacturers “will also have to figure out how they can differentiate themselves from one another,” adds Doyle of Quintiles.

PBM Cigna isn’t waiting for eventual real-world data. In May, the company announced that it had finalized “value contracts” with both Amgen and Sanofi/Regeneron, to tie the negotiated price of these two new PCSK9 inhibitors directly to improved patient health. Specifically, if the drugs meet or exceed expected LDL-C reduction across Cigna’s broad patient base, the negotiated price remains in place; if the patients are not able to reduce LDL cholesterol levels as expected, the two drugmakers will further discount the cost of the drugs, explains Christopher Bradbury, SVP, Integrated Clinical and Specialty Drug Solutions for Cigna Pharmacy Management. “Innovating through the contracting approach is one way we are helping our customers and clients to receive more value for their healthcare dollar, and this is important for the high-cost PCSK9 inhibitors because as prescribing grows within this class, they could impact significant numbers of patients.”

The agreements put manufacturers’ own dollars at risk,” he says, which will “introduce a new form of competition” in the market. The company is the first to strike independent, value-based agreements with both sets of manufacturers. Cigna has already had success using similar value-based contracts with pharmaceutical companies covering other high-cost medications for cholesterol, heart failure, diabetes, multiple sclerosis and hepatitis C.

Meanwhile, Express Scripts’ Cholesterol Care Value Program (CCV) “combines discounts on these PCSK9 therapies with rigorous clinical documentation and utilization-management strategies and a total cost cap for participating plans, to minimize unnecessary risks and wasteful spending, and help hold down payer’s drug spend on these medications.” With its conscientious effort, Express Scripts says its National Preferred Formulary clients collectively will spend “approximately $750 million on PCSK9 inhibitors in 2016—far lower than industry forecasts.”

Drug-device combinations

In addition to the world of oral and injectable therapies that are available to treat CVD and its underlying conditions, a host of medical devices are also available or under development to further improve interventional cardiology and endovascular care. These include:

  • Diagnostic devices—such as wearable and insertable heart-monitoring devices
  • Structural-replacement elements—such as transcatheter mitral valve replacement (TMVR), transcatheter aortic valve replacement (TAVR) devices and transcatheter pulmonary valve replacement (TPV) devices
  • Interventional devices—such as pacemakers, automated external and implanted defibrillators, stents and bioabsorbable stents and more.

Taking the concept even further, a growing number of novel drug-device combinations are also available or under development, to facilitate drug delivery. These include drug-eluting stents or balloons, drug-eluting vascular grafts, and more. “We are beginning to see a blurring of these two entities in the world of cardiovascular care,” says Pamela Froneberger, RN, BSN, Director, Healthcare Solutions for FTI Consulting (Charlotte, NC). “Pure medical devices such as pacemakers and drug-device combinations like drug-eluting stents now play different, yet synergistic roles within the care and treatment of cardiovascular disease.”

In April, a leadless, single-chambered pacemaker from Medtronic, the Micra Transcatheter Pacing System, received US approval. “The device, which will be marketed for specific atrial fibrillation patients, works similarly to other pacemakers—except that it is a self-contained device that is implanted directly into the right atrium of the heart and has no leads,” says Froneberger. “Market-adoption rates for this product will be something to watch.”

Froneberger highlights transcatheter aortic heart valve replacement as a good example of where device-based CVD care is going. [1] The valve is implanted via minimally invasive surgery—including simply passing it up an artery into the heart; and without removing the patient’s own heart valve—thus avoiding open-heart surgery and the complications that entails. Nevertheless, she says, TAVR requires a complex, multi-disciplined approach to care involving a complex team of interventional cardiologists, anesthesiologists, echo cardiographers, radiology/imaging and cardiothoracic surgeons, all of whom must effectively communicate and collaborate with each other to ensure patient success. “Most hospitals that have TAVR programs are struggling with the peer cross-collaboration piece more than the technical piece,” she adds. “They are also struggling to show positive rates of return on their program investments—especially if they are not monitoring and measuring cost per procedure/physician on a regular basis.”

Edwards Lifesciences (Irvine, CA) and Medtronic are two of the suppliers of 
the therapy.

Not surprisingly, the supply chain for medical devices and drug-device combinations used in CVD is complex. “In today’s competitive healthcare environment, the economic question for manufacturers of drug-device combination products has to be: ‘Is there a quantifiable economic value for patients to use these products above and beyond what has historically been used to treat a particular disease?’” says Froneberger of FTI Consulting. “To the hospital that purchases these products, the question becomes: ‘If we buy this drug-device combination product instead of the earlier non-drug model, how much more are we going to pay? And, will we get our money back or lose our shirt?”

“Unless there are credible, peer-reviewed articles on the drug-combo products—that are not sponsored or funded by the manufacturer—medical devices, both drug-combo or not, are bumping up against market-entry barriers like never before, making mass market adoption rates more difficult,” says Froneberger, adding: “If manufacturers aren’t answering these questions themselves months or years before the product moves from the conceptual drawing board to the hospital’s loading dock, they are likely to see their product traverse a journey to nowhere land.”

Merger mania in the CVD device space

A wave of recent mergers in the CVD medical device space signals the partners’ intentions to exploit the natural synergies that exist between CVD drugs, medical devices and drug-device combination products, and industry observers say that such consolidation gives merged entities better bargaining power with hospitals.

In April 2016, Abbott agreed to purchase heart-device manufacturer St. Jude Medical for $25 billion. According to the companies, St. Jude Medical’s strong positions in heart failure devices, atrial fibrillation and cardiac rhythm management complement Abbott's leading positions in coronary intervention and transcatheter mitral repair.
In March 2016, Johnson & Johnson announced that pending regulatory approval, it is acquiring NeuWave Medical, a privately held medical device manufacturer.
  • Medtronic plc recently made two strategic acquisitions in the medical devices field: In August 2015, it acquired Twelve, a Redwood City, CA-based developer of a still-in-development transcatheter mitral valve replacement device, for $458 million, and in July 2015, Medtronic acquired Carlsbad, CA-based medical device maker RF Surgical Systems for $235 million.
CVD drug access

Because the risk factors for heart disease and stroke are so directly impacted by lifestyle choices, patient-support initiatives play a critical role in reducing the long-term risks (and costs) of CVD through the proper management of threat factors such as diet and exercise, obesity, high cholesterol levels, tobacco and alcohol use, and sustained adherence to medications (especially those required indefinitely to manage chronic conditions). When it comes to costly biologics and other specialty medications, comprehensive patient-support programs are often administered through a centralized, branded hub, which combine a mix of high-tech and high-touch program elements to educate patients and providers, remove financial and clinical barriers to access, and support long-term adherence.

For instance, hub programs often help patients to verify insurance reimbursement and remove financial barriers by connecting them with branded coupons and copay-offset coupons that can reduce out-of-pocket costs for medications, or helping them to enroll in patient assistance programs for which they may be eligible, to access the drug at no cost.

“With access and reimbursement being such a huge hurdle for so many patients, brand teams must remember that the copay card is really just the starting point for engagement with patients—the real work starts in terms of how you continue to engage them beyond Month 1, 2 or 3,” says Javier Castillo, executive director of Program Strategy and Design for the Health Management Solutions (HMS) group of Quintiles.

“Clinical nurse-educators, providing individual training or interacting with patients and caregivers through virtual webinars and group settings, provide a particularly effective way to educate enrolled patients, helping them to understand their disease and their medications and to stay on therapy, even if the condition is asymptomatic, as is so often the case in CVD,” he adds.

Targeting physicians with support tools is equally important. With today’s newer, high-cost CVD medications, “physicians often encounter complex payer requirements for patient medical histories, prior authorizations and more, which can create a significant administrative hurdle and administrative restrictions that must be overcome before a patient can start therapy,” says Kleinrock of IMS Institute.

“Branded hubs continue to provide an effective way to give patients and prescribers access to a number of tools to manage the many utilization restrictions that are imposed by payers to control costs and reduce inappropriate prescribing,” adds Cothran of Lash Group. “Program elements may include easy phone access to trained specialists who can coach prescribers and their staffs through the complex prior authorization (PA) and step therapy protocols and related documentation, and the ability to leverage electronic PA tools that can streamline the process.”

“Throughout CVD, there’s quite a need for education up front and the practice often needs tools to support the patient,” says Castillo of Quintiles. “It’s really important to develop programs that target the doctor, nurse, family nurse practitioner and physician assistant, so they are aware that the product’s support programs go way beyond just the copay-assistance card. You get a much higher level of enrolled and engaged patients when it’s the healthcare professional who is recommending enrollment in the program. At the end of the day, hub programs are only as good as the volume of patients that are being driven through them.”

A big part of patient support is changing lifestyle habits in conjunction with the drug or surgical interventions. “Specifically for CVD patients, many patients have a history of poor eating and exercise habits, do not seek routine healthcare and are not very good about taking their medications,” says Amanda Dean, PMP, account manager with Triplefin. “When a patient is prescribed a medication (for instance, an oral anti-platelet agent following a CVD event), it’s really critical to develop programs and support tools that help the patient understand that they must now manage a chronic condition—not just that they had a heart attack and the doctor has fixed it.”

“Patients who have had a heart attack have scared themselves and they’ve scared their families, so the contact center professionals try to capitalize on this during coaching sessions, by, for instance, helping patients truly understand what their chronic medication is able to do for them,” she adds.

“Because of their clinical experience and patient focus, nurses are not only able to provide standardized, program-specific information but they can also pick up on subtle cues, probe further and assess the patient, personalizing an approach based on individual needs,” adds Castillo of Quintiles.

Who picks up the tab?

Traditionally, high-tech and high-touch patient-support programs that have been the domain of drug manufacturers (and their third-party partners) offering high-cost, high-complexity specialty medications. However, an interesting conundrum emerges within cardiovascular disease—because the need for constant hand-holding is high, yet the majority of the drugs that are used today to treat high cholesterol and high blood pressure are now generic.

In light of this disconnect, many PBMs, including both Cigna and Express Scripts, and disease-specific groups such as the American Heart Assn., some advanced healthcare systems and others, have stepped into the breach, offering a variety of online programs, and clinical, and health and behavioral coaching support, to promote wellness and medication adherence for patients.

“Patient support programs definitely tend to dwindle to just copay support for many generics, since there is no real profit margin available—these types of robust support programs still fall to the branded manufacturers,” says Castillo of Quintiles. “In fact, for brands that are approaching patent expiry, these valuable adherence-related programs can help to differentiate the branded drug against the generic in the eyes of physicians, and may help to preserve some market share once the generics enter the market.”

“We take a comprehensive approach to supporting patients with cardiovascular conditions, whether they are using a generic or specialty drug, as our focus is on improving overall health and total healthcare costs,” adds Bradbury of Cigna. “For instance, we work directly with our customers through many channels, engaging not only patients but physicians. We help customers understand the risk factors of non-adherence, develop healthier behaviors and provide insight so that physicians can help to address those blind spots.”

Drug shortages woes

Drug shortages have been a pervasive and persistent problem impacting the US healthcare landscape in recent years. The number of active shortages of “medically necessary drugs” in the US has increased more than sevenfold since 2007, and such shortages can last for months or even years. A significant number of the drugs impacted by shortages include those used to treat cardiovascular patients.

“Shortages of cardiovascular drugs have become increasingly common, representing an ongoing public health crisis,” stated Brent Reed, PharmD, of the University of Maryland School of Pharmacy, in a recent American Heart Journal article. [2] “They have become a familiar aspect of contemporary clinical practice, especially in acute and critical-care settings, where complex clinical decisionmaking can be further compounded by limited access to common standards of care.”

Drug shortages can lead to delays or denial of treatment for patients, medication rationing (which raises obvious ethical concerns), and substitution of alternatives therapies that are often not identical. “When evidence-based alternatives do not exist, clinicians are forced to second- or third-line therapies, which may be less effective or confer a greater risk of adverse events or dosing errors,” says Erin Fox, PharmD, FASHP, director of the University of Utah Drug Information Service (UUDIS). She notes that medication errors are much more likely to occur when a different drug, dosage, strength or formulation, or drugs with different labels or different administration routes, must be substituted. “With so many patients impacted by CVD, ongoing shortages create major medical implications,” she adds.

According to FDA, 65% of all drug shortages are caused by manufacturing and quality issues and failure to comply with current Good Manufacturing Practices (cGMP). “The economics are definitely on the side of the branded products and they have the money to build in some redundancy and they have a vested interest in not engendering bad press,” says Fox. “FDA should implement a metric—with real financial incentives and penalties—that would incentivize and reward companies to strive for the highest quality standards to enhance the reliability of their suppliers. Right now, it’s pass/fail on quality—you’re either on the market or you’re not.”

Fragile drug supply chain

After excluding electrolytes and intravenous fluids, UUDIS data indicates that one out of every 10 shortages from Jan. 1, 2001 to Sept. 30, 2014 involved drugs used in the management of CVD. Of the 181 shortages involving cardiovascular drugs, the majority (68%) represented therapies used in the routine management of CVD (such as vasodilators and other antihypertensives, antiarrhythmics and diuretics). Another 19% represented drugs related to coagulation, thrombosis, or flood formation (such as heparin), and 13% represented vasoactive drugs (such as dopamine, norepinephrine), which are required in critically ill patients, says Fox of UUDIS, who co-authored the American Heart Journal article. The situation is especially troubling within the realm of CVD, she says, because so many of the drugs in question are very clear first-line therapies—such as nitroglycerin, heparin, epinephrine and others—and have few, if any evidence-based alternatives.

Dosing errors

Critical shortages of intravenous (IV) nitroglycerin began to emerge in early 2014, impacting thousands of patients each year. “Nitroglycerin is pretty much what any patient who has a heart attack and goes to the ER is going to get,” says Fox. As part of the workaround solution devised by FDA, Arbor Pharmaceuticals began importing from Germany a formulation of nitroglycerin marketed as glyceryl trinitrate (Nitronal). “Use of this alternative raises the risk of dosing errors, due to the use of a different concentration of this drug compared to the traditional US product,” says Fox.

In a similar vein, according to FDA [3], a 2010 survey of pharmacy directors showed that the annualized personnel costs associated with managing drug shortages across US hospitals is estimated at $216 million/year, in terms of time spent by physicians, pharmacists and nurses on tasks such as investigating alternative agents, developing action plans, managing inventory, adjusting computer systems to use alternative agents and educating staff. Fox of UUDIS notes that this estimate is conservative, as it relates only to costs incurred by hospitals but not all venues impacted by drug shortages (such as ambulatory infusion centers, community pharmacies and long-term care facilities), and the number of persistent drug shortages is higher now than it was during the survey period.

Expedited reviews

Part of the FDA Safety and Innovation Act (FDASIA) of 2012 expanded FDA’s regulatory authority and specifically requires manufacturers to notify the agency at least six months in advance (or as soon as practicable) of any interruptions or discontinuations in the production of critical drugs. FDASIA empowers FDA to use tools such as expedited reviews of new applications for generic drugs, increased regulatory discretion, and other market and manufacturing interventions to identify alternate manufacturers who might be able to ramp up production to reduce the magnitude or duration of 
the shortage.

Since the enactment of FDASIA, early warning notifications from manufacturers to FDA have increased six-fold, and “the lead time gives FDA at least a fighting chance to step in and see if it can get other manufacturers to step up to address the pending shortage,” says Fox. And this has yielded some impressive results: FDA was able to circumvent 282 drug shortages in 2012, 170 drug shortages in 2013, 101 drug shortages in 2014, and 128 drug shortages in the first three quarters of 2015, according to the 2015 annual report to Congress [4].


  • Froneberger, Pamela, FTI Clinical Passport—2015 Product Trends in Cardiovascular and Endovascular Care, FTI Consulting White Paper, March 2015, Accessed at:
  • Reed, Brent N., Fox, Erin R., et al, The Impact of Drug Shortages on Patients with Cardiovascular Disease: Cause, Consequences and a Call to Action, American Heart Journal, May 2016, Vol. 175, pp. 130–141;
  • U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Approach to Addressing Drug Shortage; Public Workshop,, 26 September 2011.
  • Dept. of Health and Human Services and FDA, Third Annual Report on Drug Shortages for Calendar Year 2015.







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