FDA Approves First Drug For Spinal Muscular Atrophy

 

Spinal muscular atrophy (SMA), is a hereditary disease that causes weakness and muscle wasting because of the loss of lower motor neurons controlling movement. There is wide variability in age of onset, symptoms and rate of progression. SMA types 1 through 4 all result from a single known cause – a deficiency of a protein called SMN, for “survival of motor neuron.“ Deficiency of SMN protein occurs when a mutation is present in both copies of the SMN1 gene one on each chromosome 5. When SMA symptoms are present at birth or by the age of 6 months, the disease is called type 1 SMA (also called infantile onset or Werdnig-Hoffmann disease). Babies typically have generalized muscle weakness, a weak cry and breathing distress. They often have difficulty swallowing and sucking, and don’t reach the developmental milestone of being able to sit up unassisted. Typically these babies have two copies of the SMN2 gene, one on each chromosome 5. Over half of all new SMA cases are SMA type 1. When SMA has its onset between the ages of 7 and 18 months and before the child can stand or walk independently, it is called type 2 or intermediate SMA. Children with type 2 SMA generally have at least three SMN2 genes. Late-onset SMA (also known as types 3 and 4 SMA, mild SMA, adult-onset SMA and Kugelberg-Welander disease) results in variable levels of weakness. Type 3 SMA has its onset after 18 months, and children can stand and walk independently, although they may require assistance. Type 4 SMA has its onset in adulthood, and people are able to walk during their adult years. People with types 3 or 4 SMA generally have between four and eight SMN2 genes, from which a fair amount of full-length SMN protein can be produced.

 

The FDA has approved Spinraza (nusinersen) for use across the range of SMA patients. Spinraza is the first drug approved to treat children and adults with SMA, is administered by injection into the fluid surrounding the spinal cord. The efficacy of Spinraza was demonstrated in a clinical trial in 121 patients with infantile-onset SMA who were diagnosed before 6 months of age and who were less than 7 months old at the time of their first dose. Patients were randomized to receive an injection of Spinraza, into the fluid surrounding the spinal cord, or undergo a mock procedure without drug injection (a skin prick). Twice the number of patients received Spinraza compared to those who underwent the mock procedure. The trial assessed the percentage of patients with improvement in motor milestones, such as head control, sitting, ability to kick in supine position, rolling, crawling, standing and walking.

 

The FDA worked closely with the sponsor during development to help design and implement the analysis upon which this approval was based. The FDA asked the sponsor to conduct an interim analysis as a way to evaluate the study results as early as possible. A total of 82 of the 121 treated patients were eligible for this analysis. Results showed that 40% of patients treated with Spinraza achieved improvement in motor milestones as defined in the study, whereas none of the control patients did. Additional open-label uncontrolled clinical studies were conducted in symptomatic patients who ranged in age from 30 days to 15 years at the time of the first dose, and in presymptomatic patients who ranged in age from 8 days to 42 days at the time of first dose. These studies lacked control groups and therefore were more difficult to interpret than the controlled study, but the findings appeared generally supportive of the clinical efficacy demonstrated in the controlled clinical trial in infantile-onset patients.

 

The most common side effects found in participants in the clinical trials on Spinraza were upper respiratory infection, lower respiratory infection and constipation. Warnings and precautions include low blood platelet count and toxicity to the kidneys (renal toxicity). Toxicity in the nervous system (neurotoxicity) was observed in animal studies.

 

The FDA granted this application fast track designation and priority review. The drug also received orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The sponsor is also receiving a rare pediatric disease priority review voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive priority review of a subsequent marketing application for a different product. This is the eighth rare pediatric disease priority review voucher issued by the FDA since the program began.

 

Spinraza is marketed by Biogen of Cambridge, Massachusetts and was developed by Ionis Pharmaceuticals of Carlsbad, California.

 

21st Century Cures Act: Making Progress on Shared Goals for Patients

 

The following was excerpted from FDA Voice, authored by Robert M. Califf, M.D., FDA Commissioner

 

On 13 December 2016, Today, President Obama signed into law the 21st Century Cures Act, which builds on FDA’s ongoing efforts to advance medical product innovation and ensure that patients get access to treatments as quickly as possible, with continued assurance from high quality evidence that they are safe and effective. The 21st Century Cures Act will greatly improve FDA’s ability to hire and retain scientific experts as one of FDA’s ongoing challenges has been recruiting and retaining the experts needed in specialized areas to meet FDA’s growing responsibilities. This is an especially important need given the tremendous advances in biological sciences, engineering, information technology and data science. Preventive, diagnostic and therapeutic strategies will become more complex with much greater potential for benefit and in some cases greater risk if used without adequate evidence to exclude risks that exceed potential benefits.

 

This new law rightly recognizes that patients should play an essential role in the development of drugs and devices to diagnose and treat their disease, since patients are in a unique position to provide essential insights about what it is like to live with and fight their disease. That’s been FDA’s perspective as well, and it’s why FDA has continued to advance the science of patient input through its patient-focused drug development program and its partner with patients program for medical devices. As it is, 21st Century Cures will enhance these ongoing efforts to better incorporate the patient’s voice into FDA’s decision-making.

 

21st Century Cures will also support FDA’s efforts to modernize and improve efficiency in clinical trial design. This has been an important FDA priority for decades, but exciting new approaches are now available to develop a common understanding of which designs should be used for which clinical issues. In cancer, for example, FDA is already weighing the use of common control trials, which share a control arm, involve multiple different drugs for the same indication, and may even involve different companies. One of the benefits of using a common control arm is that the overall number of patients who need to be recruited and enrolled decreases, thereby optimizing clinical trial resources and potentially shortening the time it takes to get a new study off the ground.

 

Even without the benefit of Cures, patients have been well-served by FDA’s program efficiencies, emphasis on early meetings, and use of expedited pathway programs to speed approval and delivery of new drugs and devices to patients. Rather than passively processing product applications, FDA works to advise companies and inventors from the earliest stages of the development process on the kinds of medical products needed, how to do the necessary research, and how to viably and effectively translate from concept to product. This not only means that important new products will be developed as efficiently as possible but also that medicines and devices with no chance of success are identified much earlier so that money isn’t wasted on futile development. These programs have been embraced by developers of medical products in this country, and they are making a real and positive difference.

 

In the United States, the FDA uses expedited programs (fast track, priority review, accelerated approval, and breakthrough therapy) for drugs and biologics more than comparable drug and biologic regulators in other countries use theirs and as a result FDA is the first to approve a majority of novel drugs compared to foreign counterparts. For devices, this past year was the first full year of operation for FDA’s expedited access pathway (EAP) program, which helps speed the development and availability of certain medical devices that demonstrate the potential to address unmet medical needs for life-threatening or irreversibly-debilitating diseases or conditions. So far, FDA has granted 24 devices access to this program. 21st Century Cures builds on EAP by creating the breakthrough device pathway.

 

The law establishes other new programs as well. For instance, the Limited Population pathway will help streamline the development programs for certain anti-bacterials and anti-fungals intended to treat targeted groups of patients suffering from serious or life-threatening infections where unmet need exists due to lack of available therapies. Approvals of these antimicrobials are expected to rely on data primarily targeting these limited populations. The statement “Limited Population“ will appear prominently next to the drug’s name in labeling, which will provide notice to healthcare providers that the drug is indicated for use in a limited and specific population of patients. The limited population statement, additional labeling statements describing the data, and FDA review of promotional materials, will help assure these drugs are used narrowly to treat these serious and life-threatening infections while additional evidence is generated to assess safety and effectiveness for broader use.

 

21st Century Cures also creates a new program for the development of regenerative medicine products, an important and exciting new field that deserves this special focus. The program designates drugs as regenerative advanced therapies and takes appropriate actions to improve the efficiency of development and to enhance the exchange of information among FDA, researchers and developers. An especially important element of this program is the creation of a research network and a public-private partnership to assist developers in generating definitive evidence about whether their proposed therapies indeed provide clinical benefits that are hoped for.

 

Looking ahead, much still needs to be done to spur product development. There have yet to be successful therapies identified for certain diseases, such as Alzheimer’s disease, where underlying scientific knowledge is still lacking. In addition, we are only at the early stage in building a national evidence generation system based on registries, claims data, and electronic health records that will be a rich source of post-market data and an avenue for conducting more efficient research. Last week, FDA published a consensus of FDA leadership on the use of real world evidence in the New England Journal of Medicine, focusing on the misperception that randomized trials and real world data are incompatible. In fact, the use of randomization within the context of clinical practice will constitute a major advance in evidence generation and we are actively encouraging proposals with this combination of randomized trials conducted in real world practice. Cures provides support for continued exploration of the use of real world evidence in the regulatory context. The law also addresses drug firms providing healthcare economic information to payers and formulary committees. This complex area will require careful delineation of principles to guide information exchange to enable these entities to appropriately assess the value of drugs.

 

With 21st Century Cures, great progress has been made towards our shared goal of advancing regulatory science so that we can continue to speed the discovery, development, and delivery of medical products to prevent and cure disease and improve health while sustaining the evidence framework that enables assurance to the public of the safety and effectiveness of medical products. FDA now stands ready to work with Congress, other federal agencies and the medical products ecosystem to implement these important provisions as we all continue to work on behalf of all Americans to protect and promote public health and promote innovation in this exciting time.

 

FDA Takes Action Against 4 Tobacco Manufacturers for Illegal Sales of Flavored Cigarettes Labeled as Little Cigars or Cigars

 

The Tobacco Control Act, which was passed by Congress and signed by the President in 2009, banned cigarettes containing certain characterizing flavors, such as candy or fruit flavors, to reduce the number of youth who start to smoke and who become addicted to dangerous tobacco products. The FDA began enforcing that provision in September 2009.

 

The FDA has issued warning letters to four tobacco manufacturers: Swisher International Inc., Cheyenne International LLC, Prime Time International Co. and Southern Cross Tobacco Company Inc., for selling flavored cigarettes that are labeled as little cigars or cigars, which is a violation of the Family Smoking Prevention and Tobacco Control Act. The companies received warning letters for products under the “Swisher Sweets,“ Cheyenne,“ “Prime Time“ and “Criss-Cross“ brands in a variety of youth-appealing flavors, including grape, cherry, wild cherry and strawberry.

 

According to FDA, flavored cigarettes appeal to kids and disguise the bad taste of tobacco, but they are just as addictive as regular tobacco products and have the same harmful health effects. Also, because about 90% of adult daily smokers smoked their first cigarette by the age of 18, continued enforcement of the ban on cigarettes with characterizing flavors is vital to protect future generations from a lifetime of addiction.

 

The FDA determined that, although labeled as little cigars or cigars, the products meet the definition of cigarettes in the Tobacco Control Act, because they are likely to be offered to, or purchased by, consumers as cigarettes based on their overall presentation, appearance, and packaging and labeling. Additionally, since the products meet the definition of a cigarette, the FDA determined that the products are adulterated because they contain a natural or artificial characterizing flavor, or misbranded if they only purport to do so.

 

The FDA has requested the manufacturers respond to the warning letters within 15 working days of receiving the letter. Failure to obey federal tobacco law may result in the FDA initiating further action, including, but not limited to, civil money penalties, criminal prosecution, seizure, and/or injunction. The agency expects many of these products to remain available for purchase by consumers at retail establishments while the FDA works with the manufacturers to ensure the products are in compliance with the requirements of the law.

 

Consumers and other interested parties can report a potential tobacco-related violation of the FD&C Act by using the FDA’sPotential Tobacco Product Violation Reporting Form.

 

FDA Approves Jardiance to Reduce Cardiovascular Death In Adults With Type 2 Diabetes

 

According to the Centers for Disease Control and Prevention, death from cardiovascular disease is 70% higher in adults with diabetes compared to those without diabetes, and patients with diabetes have a decreased life expectancy driven in large part by premature cardiovascular death.

 

The FDA has approved a new indication for Jardiance (empagliflozin) to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and cardiovascular disease. The FDA’s decision is based on a postmarketing study required by the agency when it approved Jardiance in 2014 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Jardiance was studied in a postmarket clinical trial of more than 7,000 patients with type 2 diabetes and cardiovascular disease. In the trial, Jardiance was shown to reduce the risk of cardiovascular death compared to a placebo when added to standard of care therapies for diabetes and atherosclerotic cardiovascular disease.

 

Jardiance can cause dehydration and low blood pressure (hypotension). Jardiance can also cause increased ketones in the blood (ketoacidosis), serious urinary tract infection, acute kidney injury and impairment in renal function, low blood glucose (hypoglycemia) when used with insulin or insulin secretagogues (e.g. sulfonylurea, a medication used to treat type 2 diabetes by increasing the release of insulin in the pancreas), vaginal yeast infections and yeast infections of the penis (genital mycotic infections), and increased cholesterol. The most common side effects of Jardiance are urinary tract infections and female genital infections.

 

Jardiance is not intended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Jardiance is contraindicated in patients with a history of serious hypersensitivity reactions to Jardiance, severe renal impairment, end-stage renal disease, or dialysis.

 

Jardiance is distributed by Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.

 

FDA Research Helps to Speed Development of Zika Virus Vaccines and Therapeutics

 

The recent spread of the Zika virus and its association with increased rates of neurological disorders and complex congenital syndromes, such as microcephaly in babies and Guillain-Barre Syndrome in adults, has created an urgent need for animal models to examine the virus’ pathology. Better understanding the impact and long-term effects of the Zika virus infection in mice may be useful in efforts to find ways to combat it in a human population. A new mouse model developed by scientists at the U.S. Food and Drug Administration may help in exploring the potential activity of Zika virus vaccines and therapeutics. Published in PLoS Pathogens (17 November 2017), is the description of a neonatal mouse model that provides a platform for potentially improving and expediting studies to understand the causes and effects (pathology) of the Zika virus.

 

The FDA’s scientists found that neonatal mice of the C57BL/6 mouse strain are susceptible to the Zika virus and develop neurological symptoms 12 days post infection. These mice eventually recover from disease and thus the model provides an opportunity to study the virus’ long-term effects as well as an additional means for early exploration of experimental Zika virus vaccines and therapeutics. This advancement is just one of many research projects the FDA has undertaken as part of the agency’s comprehensive effort to fight the Zika virus. For example, the FDA has invested in initiatives to understand the effectiveness of technologies that reduce pathogens (such as viruses or other microorganisms that can cause disease) in blood, evaluate the impact of red blood cell storage on virus infection, expand the agency’s database of virus-infected samples essential to the development of diagnostic devices, and explore how long the Zika virus persists in body tissues, among other projects.

 

In addition to advancing research initiatives, the FDA is also working rapidly in a variety of areas to respond to the emerging Zika virus outbreak. The agency’s activities are focused on protecting the safety of our nation’s supply of blood and human cells, tissues and cellular and tissue-based products, encouraging development of diagnostic tests to help clinicians detect and diagnose Zika virus infection, and evaluating the safety and efficacy of any investigational vaccines and therapeutics that are currently in various stages of early development.

 

FDA Grants Accelerated Approval to New Treatment for Advanced Soft Tissue Sarcoma

 

Congratulations to our friends and colleagues at Lilly.

 

The National Cancer Institute estimates that 12,310 new cases of soft tissue sarcoma (STS) and nearly 5,000 deaths are likely to occur from the disease in 2016. The most common treatment for STS that cannot be removed by surgery is treatment with doxorubicin alone or with other drugs. STS includes a wide variety of tumors arising in the muscle, fat, blood vessels, nerves, tendons or the lining of the joints.

 

The FDA has granted accelerated approval to Lartruvo (olaratumab) in combinmation with doxorubicin, to treat adults with certain types of STS. Lartruvo is a platelet-derived growth factor (PDGF) receptor-alpha blocking antibody. When stimulated, PDGF receptors cause tumor growth. Lartruvo works by blocking these receptors, which may help slow or stop tumor growth. Lartruvo is approved for use with doxorubicin for the treatment of patients with STS who cannot be cured with radiation or surgery and who have a type of STS for which an anthracycline (chemotherapy) is an appropriate treatment.

 

The safety and efficacy of Lartruvo were studied in a randomized clinical trial involving 133 patients with more than 25 different subtypes of metastatic STS. Patients received either Lartruvo with doxorubicin or doxorubicin alone. The clinical trial measured the length of time patients lived after treatment (overall survival), the length of time tumors did not grow after treatment (progression-free survival) and the percentage of patients who experienced shrinkage of their tumors (overall response rate). Results showed that patients in this trial who received Lartruvo with doxorubicin had a:

 

1.statistically significant improvement in overall survival: the median survival was 26.5 months compared to 14.7 months for patients who received doxorubicin alone.

 

2. median progression-free survival of 8.2 months compared to 4.4 months for patients who received doxorubicin alone.

 

3. tumor shrinkage of 18.2% compared to 7.5% for those who received doxorubicin alone.

 

Lartruvo has serious risks including infusion-related reactions and embryo-fetal harm. Infusion-related reactions include low blood pressure, fever, chills and rash. The most common side effects of treatment with Lartruvo are nausea, fatigue, low levels of white blood cells (neutropenia), musculoskeletal pain, inflammation of the mucous membranes (mucositis), hair loss (alopecia), vomiting, diarrhea, decreased appetite, abdominal pain, nerve damage (neuropathy) and headache.

 

The FDA granted the Lartruvo application fast track designation, breakthrough therapy designation and priority review status because preliminary clinical evidence indicated that it may offer a substantial improvement in effectiveness in the treatment of a serious or life-threatening disease or condition. The FDA is approving Lartruvo under the agency’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease or condition based on clinical data showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. The sponsor is conducting a larger study, which is currently underway, to further explore the effectiveness of Lartruvo across the multiple subtypes of STS. Lartruvo also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs intended to treat rare diseases.

 

Lartruvo is marketed by Eli Lilly and Company based in Indianapolis, Indiana.

 

FDA Approves New Device for Prevention of Recurrent Strokes in Certain Patients

 

The cause of most strokes can be identified, such as poorly controlled high blood pressure, narrowed blood vessels due to cholesterol deposits and scar tissue (atherosclerosis), or a blood clot caused by an abnormal heart rhythm (atrial fibrillation). However, in some patients, medical tests cannot identify the cause of the stroke, which is referred to as a cryptogenic stroke. About 25-30% of Americans have a patent foramen ovale (PFO), which typically causes no health problems and does not require treatment. However, in a small percentage of these patients, it is believed that the PFO provided a path for a blood clot to travel to the brain where it blocked a blood vessel resulting in a stroke. As a result, patients with a cryptogenic stroke and a PFO may be at an increased risk of having a second stroke.

 

The FDA has approved the Amplatzer PFO Occluder device to reduce the risk of a stroke in patients who previously had a stroke believed to be caused by PFO, and then traveled to the brain. The device is inserted through a catheter that is placed in a leg vein and advanced to the heart. It is then implanted close to the hole in the heart between the top right chamber (right atrium) and the top left chamber (left atrium). The device had been on the market more than a decade ago under a humanitarian device exemption (HDE), but was voluntarily withdrawn by the manufacturer in 2006 after the FDA concluded that the target population for this device was greater than 4,000 patients and that the device no longer qualified for an HDE approval. For the past 10 years, no FDA-approved heart occluder devices have been on the market specifically indicated to close PFOs to reduce the risk of a recurrent stroke in patients with a prior cryptogenic stroke.

 

In approving the Amplatzer PFO Occluder, the FDA concluded that the device demonstrated a reasonable assurance of safety and effectiveness. The safety and efficacy was assessed in a randomized study that evaluated 499 participants aged 18 to 60 years old who were treated with the Amplatzer PFO Occluder plus blood-thinning medications compared to 481 participants who were treated with blood-thinning medications alone. While the rate of new strokes in both treatment groups was very low, the study found a 50% reduction in the rate of new strokes in participants using the Amplatzer PFO Occluder plus blood-thinning medications compared to participants taking only blood-thinning medications. Adverse effects associated with the device or the implantation procedure include injury to the heart, irregular and/or rapid heart rate (atrial fibrillation), blood clots in the heart, leg or lung, bleeding and stroke.

 

The Amplatzer PFO Occluder device should not be used in patients with a heart valve infection or other untreated infections, or a heart tumor or blood clot at the implant site. The device is also contraindicated in patients with other abnormal connections between the heart chambers or in whom the cardiovascular anatomy or blood clots would interfere with the ability to move the catheter used to deliver the device to the heart. Patients should discuss with their medical team (consisting of a neurologist and a cardiologist) the risks and benefits of PFO closure in comparison to using medications alone.

 

The Amplatzer PFO Occluder device is manufactured by St. Jude Medical Inc. based in Plymouth, Minnesota.

 

FDA is Working with Hospitals to Modernize Data Collection About Medical Devices

 

Extracted from FDA Voice by Jeffrey Shuren, M.D., J.D., Director of FDA’s Center for Devices and Radiological Health

 

Throughout their work day, hospital staff use a variety of medical devices: imaging machines, EKGs and in vitro tests to make diagnoses; infusion pumps, ventilators and robotics to provide treatment, and an array of implants to replace diseased joints and organs. And, as the nation’s hubs for real-time health care data, hospitals are uniquely positioned to help identify new safety problems with devices  as well as changes in the frequency of already known safety problems. The reason is that hospitals use these technologies in the real-world setting of clinical practice, outside of the more controlled setting of a clinical trial. FDA is looking to improve the way we work with hospitals to modernize and streamline data collection about medical devices.

 

FDA’s evaluation of medical device safety presents unique challenges not seen with drugs and biologics, given: 1) the greater diversity and complexity of medical devices today; 2) the rapid technological advances and iterative nature of medical device product development; 3) the interface between the technology and the user; and, 4) in some cases, a relatively short product life cycle that can be measured in months, not years. Therefore, assuring the safety of medical devices depends on many factors and should a problem arise, it could be due to a variety of causes.

 

At the time of premarket evaluation, however, it is not feasible to identify all possible risks or to have absolute certainty regarding a technology’s benefit-risk profile. The reaon is that  studies required to do so would likely be prohibitively large in order to capture less frequent and more unpredictable effects or consequences. In addition, such larger studies still may not reflect the true benefit-risk profile of the device. Once a device is on the market, for example, doctors may use it beyond the FDA cleared intended use. In addition, subsequent modifications to the device or changes in how the device is used in practice can result in new safety risks or greater frequency of known risks.

 

FDA has several tools for watching devices once they are on the market, all of which have inherent limitations. For one thing, FDA can require that a manufacturer conduct a post-approval or postmarket surveillance study that focuses on identifying potential longer-term issues noted at the time of clearance or approval or specific safety concerns that may arise after clearance or approval. However, conducting studies on a product after it’s already on the market can be challenging because patients often have little incentive to enroll in a study when the device is already available to them. Likely the most well-known of FDA’s postmarket surveillance tools is medical device reporting, which FDA requires from certain entities, including device manufacturers and device user facilities, such as hospitals.

 

Federal law requires hospitals and other user facilities to report when they become aware of information reasonably suggesting that a medical device has or may have caused or contributed to a death or serious injury to a patient. These facilities must report these medical device-related deaths to both FDA and the manufacturer, if known; and device-related serious injuries to the manufacturer, or to FDA, if the manufacturer is not known. Such passive surveillance has important limitations because it relies on people to identify that a harm occurred or a risk is present, recognize that the harm or risk is associated with the use of a particular device, and take the time to report it.

 

Congress mandated this reporting by user facilities in 1990 to complement similar adverse event reporting by manufacturers. But then, in 1997, Congress required that FDA establish a reporting program that could limit user facility reporting to a subset of representative user facilities. As part of our efforts to develop this reporting program, FDA set up a large-scale network of about 300 hospitals, called MedSun (the Medical Product Safety Network), with whom FDA works interactively to better understand and report on device use in the real-world environment. Even with MedSun, all hospitals were required to continue reporting until FDA implements by regulation a program limiting user facility reporting to a subset of facilities. Although FDA has recognized that requiring all hospitals and other user facilities to report may provide limited added value and could entail unnecessary costs that take away from patient care, FDA has not yet established the program limiting reporting to a subset of user facilities. In the past, FDA has also not enforced universal reporting requirements for hospitals and other user facilities. In light of several high-profile device safety issues occurring in hospitals, FDA, in December 2015, initiated inspections at 17 hospitals, chosen because there were reports of events at these facilities related to the spread of uterine cancer from the use of morcellators or the spread of infections associated with contaminated duodenoscopes. While these events appeared to be the kind that would have fallen under our current medical device reporting requirements, FDA did not see corresponding adverse event reports in its adverse event (MAUDE) database. From those inspections, FDA learned three important lessons:

 

First, some hospitals didn’t submit required reports for deaths or serious injuries related to devices used at their facilities, and in some cases, they did not have adequate procedures in place for reporting device-related death or serious injury events to FDA or to the manufacturers. Based on the number of user facilities in the United States and the number of reports FDA receives, FDA believes that these hospitals are not unique in that there is limited to no reporting to FDA or to the manufacturers at some hospitals. FDA wants to work with all hospitals to address these issues.

Second, hospital staff often were not aware of nor trained to comply with all of FDA’s medical device reporting requirements.

Third, FDA feelsthat there is a better way to work with hospitals to get the real-world information it needs.

Fourth, FDA should work with the hospital community to find that right path, especially in light of developments in the creation and evaluation of electronic health information.

In order to effectively address these issues, FDA will work with the hospital community on what role they should play in assuring the safe use of medical devices. This work will include how they can effectively participate in the National Evaluation System for health Technology (NEST), and whether or not current reporting requirements should remain, be modified, or eliminated in light of more effective modern tools, such as software tools to conduct active surveillance of electronic health information that contain unique device identifiers. In many cases, FDA inspections of these 17 hospitals turned up violations of FDA’s medical device reporting regulation. For some hospitals with significant violations of the regulation, FDA received a response that FDA determined was not adequate to address those violations, and FDA engaged with these facilities to facilitate an effective path to compliance. These hospitals indicated their willingness to work with FDA and address the violations, and at this time, FDA does not believe any additional action with regard to these hospitals is necessary. Some hospitals also expressed willingness to work with FDA on more efficient and effective ways to collect the information FDA needs.

 

On December 5, FDA will hold a public workshop to solicit input and advice on improving hospital-based surveillance systems, and the broader role of using hospitals to evaluate how well devices work in the clinical setting. FDA is encouraging all hospital stakeholders – from clinicians to IT system managers – to attend and discuss current hospital-based surveillance efforts, the role of hospitals in evidence generation and future opportunities for hospital-based surveillance. FDA would also like input on the incorporation of unique device identifiers (UDIs) into electronic health records to aid in the future development of evidence generation efforts, including the support of better device development, surveillance and health care delivery. FDA is already working directly with the Association of American Medical Colleges and the American Hospital Association to prepare for this workshop and help develop improvements to FDA systems.

 

FDA has made it very clear that hospitals are our partners in building the infrastructure for NEST. Together all stakeholders can build a state-of-the-art system that not only quickly identifies life-threatening problems caused by medical devices but also expedites patient access to crucial life-saving devices. Armed with such information, health care providers can help patients make more informed medical decisions that improve their health.

 

FDA/EMA Initiate Rare Diseases and Patient Engagement Clusters

 

Dr. Jules Mitchel, President of Target Health, had the honor to be on a panel with Dr. Jonathan Goldsmith at the annual NORD meeting this past week.

 

The following was posted on October 18, 2016 by FDA Voice and authored by Jonathan Goldsmith, M.D., FACP, and Sandy Kweder, M.D., RADM (Ret.) US Public Health Service:

 

Drug development and approval happens across the globe and FDA strives to collaborate with other countries and international regulatory agencies to ensure public health. One of FDA’s most valuable collaborators is the European Medicines Agency (EMA) – its counterpart agency for drug regulation in Europe that coordinates a network of 4,500 scientists and evaluates and supervises medicines for more than 500 million people in 31 countries.

 

For more than a decade, FDA and EMA scientists have collaborated to help solve some of our biggest challenges. FDA works with them in groups called “clusters.“ The first cluster was initiated in 2004. Since then clusters have been formed to focus on treatments for children; establish effective measures for the development and use of biosimilar medications as cost effective alternatives to brand name biologic drugs; evaluate new treatments for patients with cancer; set standards to help develop medicines personalized to a patient’s genetic makeup, and much more. Both agencies have benefited from this joint work. The EMA summarizes these and our other clusters on its website.

 

Just last month FA and EMA established a cluster that will work to advance treatments for patients with rare diseases. This cluster’s primary goal is for FDA and EMA scientists to share valuable information about their work and to collaborate on certain review aspects of rare disease drug development programs. FDA’s core members of the cluster include experts from FDA’s Center for Drug Evaluation and Research’s Rare Diseases Program, the Office of Pediatric Therapeutics, the Center for Biologics Evaluation and Research’s director’s office, and the Office of Orphan Products Development, but other experts will be engaged on specific topic areas as the cluster evolves. Among many other important activities, our agencies will collaborate on:

 

1. Identification and validation of trial end points;

2. Potential trial designs when only small populations of patients are available for testing the safety and effectiveness of prospective new therapies;

3. Ways to apply flexibility in evaluation of drug development programs;

4. Expediting the review and approval of drugs to treat rare diseases to bring new drugs to patients in need as soon as possible.

 

FDA and EMA’s work also builds on another exciting and recent development – a patient engagement cluster formed in June 2016 to incorporate the patient’s involvement and viewpoint in the drug development process. FDA and EMA are interested in understanding patient’s experiences and gaining input on their tolerance for risk and uncertainty, on current therapy and its benefits or shortcomings and on the benefits that patients seek. This cluster, among other valuable efforts, will:

 

1. Help each agency learn how the other involves patients in their work, and to develop common goals of expanding future engagement activities with patients;

2. Discuss ways for finding patients that can serve as spokespersons for their community;

3. Explore ideas to help train selected patients and advocates to effectively participate in agency activities, and;

4. Develop strategies for reporting the significant impact of patient involvement.

 

Given the focus of both of these new clusters, FDA expects that they will address new areas of interest and also draw on expertise from all of the other clusters, such as oncology, pediatrics, and orphan diseases, contributing to more advanced and robust collaborations across both of our organizations. Focusing on patients with rare diseases and working to advance patient input enhances the value of the cluster activities. And finally, it is hoped that with their colleagues at the EMA, each can accomplish more together than what could be done individually.

 

Jonathan C. Goldsmith, M.D., FACP, FDA’s Associate Director, Rare Diseases Program, Center for Drug Evaluation and Research, Office of New Drugs

Sandra Kweder, M.D., Rear Admiral (Ret.) US Public Health Service, FDA’s Deputy Director, Europe Office, and Liaison to European Medicines Agency

 

Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices

 

There has been a lot of misunderstanding by non-software quality assurance professionals about the definition of “software validation.“  The definition Target Health Inc. was  taught, by experts, at the time we started software development in the late 1990’s, was that “validated software acts as intended.“  Fortunately, FDA has defined validation in the draft guidance and it is as follows.

 

“One component of design validation is software validation. Software validation refers to establishing, by objective evidence, that the software conforms with the user needs and intended uses of the device. Software validation is a part of design validation of the finished device. It involves checking for proper operation of the software in its actual or simulated use environment, including integration into the final device where appropriate. Software validation is highly dependent upon comprehensive software testing and other verification tasks previously completed at each stage of the software development life cycle. Planning, verification, traceability, configuration management, and many other aspects of good software engineering are important activities that together help to support a conclusion that software is validated.“

 

FDA has issued a draft guidance entitled “Content of Premarket Submissions for Software Contained in Medical Devices The draft Guidance provides information to industry regarding the documentation that FDA recommends that companies include in premarket submissions for software devices, including stand-alone software applications and hardware-based devices that incorporate software. This document is a result of ongoing efforts to state FDA’s recommendations more clearly and ensure they remain current as technology advances. This document supersedes Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices, issued May 29, 1998, and Reviewer Guidance for a Premarket Notification Submission for Blood Establishment Computer Software, issued January 13, 1997.

 

For the purposes of this document, FDA refers to devices that contain one or more software components, parts, or accessories, or are composed solely of software as “software devices,“ including:

 

1. Firmware, the permanent software programmed into a read-only memory, as well as other means for software-based control of medical devices

2. Stand-alone software applications

3. Software intended for installation in general-purpose computers

4. Dedicated hardware/software medical devices.

5. Accessories to medical devices when those accessories contain or are composed of software.

 

This guidance applies to software devices regardless of the means by which the software is delivered to the end user, whether factory-installed, installed by a third-party vendor, or field-installed or -upgraded. Software not covered by this guidance includes software designed for manufacturing or other process-control functions but not intended for use as a device.

 

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