Real World Evidence (RWE) and Real World Data (RWD)

 

On August 30, 2017, the U.S. Food and Drug Administration released a final guidance document on the Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices. This guidance clarifies how the agency determines whether real-world data may be sufficient for use in regulatory decisions, without changing the evidentiary standards FDA uses to make those decisions. It clarifies how FDA plans to evaluate real-world data to determine whether it may be sufficiently relevant and reliable for various regulatory decisions, and it also clarifies when an Investigational Device Exemption (IDE) may be needed to collect and use real-world data for purposes of determining the safety and effectiveness of a device.

 

Real-world data, which relate to patient health status and/or the delivery of health care routinely collected from a variety of sources, can provide powerful insight into the benefits and risks of medical devices, including how they are used by health care providers and patients. This guidance is a cornerstone of FDA’s strategic priority to build a national evaluation system for health technology (NEST).

 

On October 10, 2017 from 1:00-2:30pm EST, the FDA will hold a webinar about this guidance. 

Registration is not necessary.

 

To hear the presentation and ask questions: Dial: 800-779-8625; passcode: 7388850 | International: 1-210-234-0098; passcode: 7388850

To view the slide presentation during the webinar:

More information about this webinar or our complete webinar series can be found on the Medical Device Webinars and Stakeholder Calls webpage.

 

Following the conclusion of the webinar, you will be able to complete a brief survey about your FDA medical device webinar experience. The survey can be found at www.fda.gov/CDRHWebinar immediately following the conclusion of the live webinar.

 

If you have general questions about this guidance, please contact the Division of Industry and Consumer Education (DICE) in the Center for Devices and Radiological Health (CDRH) at 1-800-638-2041 or 301-796-7100 or dice@fda.hhs.gov.

 

Making Advances Against Sickle Cell Disease

 

The following was abstracted from FDA Voice posted on September 26, 2017

 

The medical definition of sickle cell disease – a group of inherited red blood cell disorders caused by abnormal hemoglobin, called hemoglobin S or sickle hemoglobin, in red blood cells – does not come close to describing the condition from the patient’s perspective. Sickle cell disorders have devastating effects on patients and their families. Patients often experience recurrent episodes of excruciating pain, or sickle cell crisis, debilitating fatigue, infections, cognitive disorders, strokes, a life-threatening condition called acute chest syndrome, and damage to their vital organs, tissues, and bones. In some patients, the disease may trigger frequent and very painful sickle cell crises that require hospitalization. In others, it may cause less frequent and milder attacks. Although mortality during childhood has improved progressively, the life expectancy among individuals with sickle cell disease in the United States is on average 30 years less than the general population.

 

Sickle cell is a rare disease. According to the Centers for Disease Control and Prevention, about 1 of every 365 African-Americans and about 1 out of every 16,300 Hispanic-Americans are born with sickle cell disease. In addition, more than 2 million people carry the sickle cell gene that enables them to possibly pass the disease on to their children. Today, bone marrow transplantation offers the only potential cure for this disorder; but finding a donor is difficult and the procedure has serious risk.

 

As Sickle Cell Awareness Month comes to a close this September, FDA reports on how much must be done to help patients in need and educate others on sickle cell disease – and also to recognize progress and hope for a better future.

 

In July, FDA approved Endari (L-glutamine oral powder) to reduce the severe complications from the blood disorder in patients age 5 years and older. Endari is only the second FDA-approved treatment for this disorder and the first since hydroxyurea was approved nearly 20 years ago. Studies showed that patients taking Endari experienced fewer trips to the emergency room and fewer hospitalizations for sickle cell pain than those given a placebo. They also had fewer occurrences of acute chest syndrome. Common side effects include constipation, nausea, headache, abdominal pain, cough, pain in the extremities, back pain, and chest pain.

 

FDA continues to work with all interested parties in improving the lives of patients with sickle cell disease. In February 2014, FDA held the first ever federal meeting with patients as part of our Patient Focused Drug Development program. A highlight was learning what symptoms bothered patients the most in their daily lives – the sort of information that can help inform the development and use of patient reported outcomes. And for the past several years, FDA clinical review staff has organized meetings to facilitate drug development in sickle cell disease. During these events, academic researchers, clinicians and FDA have engaged in an interactive discussion on trial design, potential endpoints, and patient reported outcomes.

 

Sickle cell disease describes a group of inherited red blood cell disorders caused by abnormal hemoglobin, the protein that carries oxygen throughout the body. Normal hemoglobin moves easily through blood vessels, but sickle hemoglobin can be crescent or sickle shaped, which causes it to stick on vessel walls, blocking or stopping the flow of blood. (Source, FDA Blog)

 

It is not entirely clear why progress in developing treatments for sickle cell disease has been slow. One challenge has been the multi-faceted nature of sickle cell disease as well as difficulty in defining biochemical endpoints and targets of clinical benefit in clinical trials. But there is hope. Since 2010, FDA has seen a rise in the number of industry meetings, clinical trial development and investigational new drug (IND) submissions for sickle cell disease (required when companies want to conduct clinical trials of an investigational new drug), which may qualify for an expedited approval program known as Fast Track. Patient-reported outcome measures are being incorporated into clinical trials for new products. Currently 143 clinical trials (on Clinicaltrials.gov) are recruiting patients studying drug interventions, gene therapy, behavioral treatment and diagnostic testing in both adults and children.

 

While the Center for Drug Evaluation and Research (CDER) work to encourage drug development, other efforts are underway to make bone marrow transplantation accessible to more patients as well as utilizing gene editing which can provide a permanent cure for sickle cell disease by correcting the sickle mutation in the stem cells. FDA knows there is much more work to be done, but FDA says it is proud to say during this Sickle Cell Awareness Month, that we are part of a dynamic team and remain committed to promoting the development of safe and effective treatments for this blood disorder.

 

For more information, please visit: The FDA Encourages New Treatments for Sickle Cell Disease

 

FDA Approves First Biosimilar for the Treatment of Cancer

 

Biological products are generally derived from a living organism and can come from many sources, such as humans, animals, microorganisms or yeast. A biosimilar is a biological product that is approved based on data showing that it is highly similar to an already-approved biological product and has no clinically meaningful differences in terms of safety, purity and potency (i.e., safety and effectiveness) from the reference product, in addition to meeting other criteria specified by law.

 

The FDA has approved Mvasi (bevacizumab-awwb) as a biosimilar to Avastin (bevacizumab) for the treatment of multiple types of cancer. Mvasi is the first biosimilar approved in the U.S. for the treatment of cancer.

 

Mvasi is approved for the treatment of adult patients with certain colorectal, lung, brain, kidney and cervical cancers. Specifically, the approved indications include:

 

1. Metastatic colorectal cancer, in combination with intravenous 5-fluorouracil-based chemotherapy for first- or second-line treatment. Mvasi is not indicated for the adjuvant treatment of surgically resected colorectal cancer.

 

2. Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrmidine-oxaliplatin-based chemotherapy for the second-line treatment of patients who have progressed on a first-line bevacizumab product-containing regimen. Mvasi is not indicated for the adjuvant treatment of surgically resected colorectal cancer.

 

3. Non-squamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent or metastatic disease.

 

4. Glioblastoma with progressive disease following prior therapy, based on improvement in objective response rate. No data is available demonstrating improvement in disease-related symptoms or survival with bevacizumab products.

 

5. Metastatic renal cell carcinoma, in combination with interferon alfa.

 

6. Cervical cancer that is persistent, recurrent, or metastatic, in combination with paclitaxel and cisplatin or paclitaxel and topotecan.

 

The FDA’s approval of Mvasi is based on review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Mvasi is biosimilar to Avastin. It has been approved as a biosimilar, not as an interchangeable product.

 

Common expected side effects of Mvasi include nose bleeds (epistaxis), headache, high blood pressure (hypertension), inflammation of the nasal cavity (rhinitis), high levels of protein in the urine (proteinuria), taste alteration, dry skin, rectal bleeding (hemorrhage), excessive tear production (lacrimation disorder), back pain and skin irritation (exfoliative dermatitis). Serious expected side effects of Mvasi include holes in or abnormal connection between two organs (perforation or fistula), blood clot formation (arterial and venous thromboembolic events), hypertension, problems in brain function or structure (posterior reversible encephalopathy syndrome), high levels of protein in the urine (proteinuria), infusion-related reactions and loss of function of the ovaries (ovarian failure). Patients should stop using Mvasi if these side effects become severe or life-threatening. Women who are pregnant should not take Mvasi because it may cause harm to a developing fetus.

 

Like Avastin, the labeling for Mvasi contains a Boxed Warning to alert health care professionals and patients about an increased risk of holes in the stomach and intestines (gastrointestinal perforations); surgery and wound healing complications; and severe or fatal pulmonary, gastrointestinal, central nervous system and vaginal bleeding (hemorrhage). Patients should stop using Mvasi if gastrointestinal perforation occurs. Patients should not take Mvasi in the 28 days prior to and after elective surgery, and until the surgical wound is fully healed. Patients should stop using Mvasi if a surgical incision breaks open (wound dehiscence). Mvasi should not be given to patients with severe hemorrhage or in patients who cough up blood (hemoptysis).

 

Health care professionals should review the prescribing information in the labeling for detailed information about the approved uses.

 

The FDA granted approval of Mvasi to Amgen, Inc. Avastin was approved in February 2004 and is manufactured by Genentech, Inc.

 

“Continuous Manufacturing” – Common Guiding Principles Can Help Ensure Progress

 

According to the FDA BLOG, authored by Michael Kopcha, Ph.D., R.Ph., FDA’s Director, Office of Pharmaceutical Quality, CDER, a new and exciting technology – continuous manufacturing (CM) – can transform the drug manufacturing process so that it is more reliable and efficient. A previous blog discussed how CM enables a much faster and more reliable manufacturing process. In some cases, manufacturing that takes a month to complete with older technology – often called batch technology – might only take days using CM. FDA is seeking input, through a public docket open until September 21, from experts in the field about the science, technology, and best practices concerning CM.

 

As with any new technology, implementing CM presents challenges, such as the initial cost of investing in new equipment. However, the CM production method offers clear benefits for both patients and industry. CM can shorten production times and improve the efficiency of the manufacturing process. CM also allows for more nimble testing and control that can help reduce the likelihood of manufacturing failures. These control strategies could potentially contribute to the prevention of drug shortages. CM technology can be implemented for an entire production process, or for specific operations within the process. Manufacturers can tailor their use of CM based on their particular product and business needs.

 

Congress has recognized the potential benefits CM can offer for drug manufacturing as well. The 21st Century Cures Act, enacted in December 2016, authorized grants to support studying CM and recommending improvements to the process of continuous manufacturing of drugs and biological products. FDA is encouraging adoption of this technology by engaging with firms interested in using CM. FDA’s Emerging Technology Team (ETT) assists companies that want to implement innovative technology, including CM, for manufacturing both new and existing drugs. FDA has already seen two companies that have implemented CM and benefited from early engagement with the ETT. Vertex has been using a CM process for their cystic fibrosis drug, Orkambi (lumacaftor/ivacaftor), since its approval in July 2015. In 2016, FDA approved a change in production from batch to continuous manufacturing for Janssen Products’ medication to treat HIV-1 infection, Prezista (darunavir).

 

With many companies now evaluating their operations for potential uses of CM, some have found specific ways to utilize CM techniques in their own production processes. As a result of these individual efforts, there are now a variety of different approaches for implementing CM technology throughout industry. Given these emerging variations, FDA’s goal is to provide a framework of principles that clarify our expectations, while still encouraging companies to innovate and implement CM. FDA is are talking with industry and are also helping lead this conversation on a global level by engaging our foreign regulatory counterparts regarding the development of clear regulatory standards. To further this effort and gather more input from experts, FDA has opened the public docketfor comment until September 21. FDA is interested in getting public feedback on published documents on this topic, including an industry-coordinated best practices document issued by the public-private consortium Center for Structured Organic Particulate Systems (C-SOPS), and white papers from a 2014 symposium published in the Journal of Pharmaceutical Sciences.

 

Assuring the availability of quality, safe and effective medications to the American public is a priority for FDA. CM, and other innovative manufacturing and control strategies, offer ways for the pharmaceutical industry to continue to help support this goal. By drawing upon the experience of FDA, industry, and academia, together, common guiding principles will be developed to support implementation of CM, building on the great progress made by industry to date.

 

FDA Approves Treatment for Chronic Graft Versus Host Disease

 

Chronic graft versus host disease (cGVHD) is a life-threatening condition that can occur in patients after they receive a stem cell transplant from blood or bone marrow, called hematopoietic stem cell transplantation (HSCT). HSCT is used to treat certain blood or bone marrow cancers. cGVHD occurs when cells from the stem cell transplant attack healthy cells in a patient’s tissues. Symptoms of cGVHD can occur in the skin, eyes, mouth, gut, liver and lungs. The condition is estimated to occur in 30-70% of all patients who receive HSCT.

 

The FDA has expanded the approval of Imbruvica (ibrutinib) for the treatment of adult patients with chronic graft versus host disease (cGVHD) after failure of one or more treatments. This is the first FDA-approved therapy for the treatment of cGVHD. The efficacy and safety of Imbruvica for the treatment of cGVHD were studied in a single-arm trial of 42 patients with cGVHD whose symptoms persisted despite standard treatment with corticosteroids. Most patients’ symptoms included mouth ulcers and skin rashes, and more than 50% of patients had two or more organs affected by cGVHD. In the trial, 67% of patients experienced improvements in their cGVHD symptoms. In 48% of patients in the trial, the improvement of symptoms lasted for up to five months or longer.

 

Common side effects of Imbruvica in patients with cGVHD include fatigue, bruising, diarrhea, low levels of blood platelets (thrombocytopenia), muscle spasms, swelling and sores in the mouth (stomatitis), nausea, severe bleeding (hemorrhage), low levels of red blood cells (anemia) and lung infection (pneumonia). Serious side effects of Imbruvica include severe bleeding (hemorrhage), infections, low levels of blood cells (cytopenias), irregular heartbeat (atrial fibrillation), high blood pressure (hypertension), new cancers (second primary malignancies) and metabolic abnormalities (tumor lysis syndrome). Women who are pregnant or breastfeeding should not take Imbruvica because it may cause harm to a developing fetus or a newborn baby.

 

Imbruvica, a kinase inhibitor, was previously approved for certain indications in treating chronic lymphocytic leukemia, Waldenstrom’s macroglobulinemia and marginal zone lymphoma, as well as under accelerated approval status for mantle cell lymphoma.

 

The FDA granted this application Priority Review and Breakthrough Therapydesignations. Imbruvica also received Orphan Drug designation for this indication, which provides incentives to assist and encourage the development of drugs for rare diseases. The FDA granted the approval of Imbruvica to Pharmacyclics LLC.

 

FDA Announces New Steps to Empower Consumers and Advance Digital Healthcare

 

The following was extracted from FDA Voice, by: Scott Gottlieb, M.D.

 

When people think about personalized medicine, they often think of genetic testing and sequencing of the human genome. But the concept of personalized medicine is much broader. It includes the re-imagination of healthcare delivery. It includes empowering consumers to take more control of their own healthcare information to make better informed decisions about their medical care and healthy living. This opportunity is enabled by a new technological paradigm of digital health tools, like apps, that enable consumers to have more active engagement and access to real-time information about their health and their activities. These tools allow consumers and providers to supersede the traditional, physical constraints of healthcare delivery and exploit the opportunities offered by mobile technology.

 

Historically, healthcare has been slow to implement disruptive technology tools that have transformed other areas of commerce and daily life. One factor that’s been cited, among many, is the regulation that accompanies medical products. But momentum toward a digital future in healthcare is advancing. Not all of these tools are subject to FDA regulation.

 

Last week, FDA announced, as part of our broader Medical Innovation Access Plan, a new component focused on digital health innovation – the formal launch of our Pre-Cert for Software Pilot Program. This new program embraces the principle that digital health technologies can have significant benefits to patients’ lives and to our healthcare system by facilitating prevention, treatment, and diagnosis; and by helping consumers manage chronic conditions outside of traditional healthcare settings. At the same time, FDA’s Center for Devices and Radiological Health (CDRH) is publishing its Digital Health Innovation Action Plan to provide details and timelines for an integrated approach to digital health technology and the implementation of the 21st Century Cures Act. By doing this, FDA is telling consumers and the digital health industry how FDA will establish clear and consistent expectations for the products FDA regulates. The challenge FDA faced in the past is determining how to best regulate these non-traditional medical tools with the traditional approach to medical product review. Now, FDA will envision and seek to develop through the Pre-Cert for Software Pilot a new and pragmatic approach to digital health technology. The method, of course, must recognize the unique characteristics of digital health products and the marketplace for these tools, so FDA can continue to promote innovation of high-quality, safe, and effective digital health devices.

 

FDA’s feels that its traditional approach to medical devices is not well suited to these products, and it needs to make sure its approach to innovative products with continual updates and upgrades is efficient and that it fosters, not impedes, innovation. Recognizing this, and understanding that the potential of digital health is nothing short of revolutionary, FDA is working toward establishing an appropriate approach that’s closely tailored to this new category of products. FDA needs a regulatory framework that accommodates the distinctive nature of digital health technology, its clinical promise, the unique user interface, and industry’s compressed commercial cycle of new product introductions.

 

This new, voluntary pilot program will enable FDA to develop a tailored approach toward this technology by looking first at the software developer or digital health technology developer, rather than primarily at the product (as FDA currently does for traditional medical products). This pilot will help FDA establish the most appropriate criteria for standing up a firm-based pre-certification program for these new tools. The goal of this new approach is for FDA to, after reviewing systems for software design, validation and maintenance, determine whether the company meets the necessary quality standards and pre-certify the company. Pre-certified companies could submit less information to us than is currently required before marketing a new digital health tool. In some cases, pre-certified companies could not submit a premarket submission at all. In those cases, the pre-certified company could launch a new product and immediately begin post-market data collection. Pre-certified digital health companies could take advantage of this approach for certain lower-risk devices by demonstrating that the underlying software and internal processes are sufficiently reliable. The post-market data could help FDA assure that the new product remains safe and effective as well as supports new uses.

 

FDA designed the new digital health pilot program to include up to nine software firms of various sizes. Initial participants in this new pilot will range from small startups to large companies that develop both high- and low-risk software products that are devices. FDA wants to include medical product manufacturers as well as non-traditional software developers. Given the amount of attention FDA is getting, and the ongoing innovation in this space, FDA is confident that there will be strong participation in the new pilot.

 

Digital health product developers will be selected for the program based on the following:

  • The company must be in the process of developing or planning to develop a software product that meets the definition of a medical device;
  • The company must have an existing track record in developing, testing, and maintaining software products and demonstrating a culture of quality and organizational excellence measures that are tracked by Key Performance Indicators (KPI) or other similar measures;
  • And during participation of the pilot, companies must agree to:
    • Provide access to measures for developing, testing and maintaining software products and demonstrating a culture of quality and organizational excellence measures by KPI;
    • Collect real-world post-market data and provide it to FDA;
    • Meet with FDA for real-time consultation;
    • Be available for site visits from FDA officials; and,
    • Provide information about the firm’s quality management system.

 

FDA has intentionally left the initial criteria broad because this pilot is purposely designed to be inclusive and flexible. FDA wants to be able to accommodate a broad range of participants and technologies. FDA also appreciates that the experience and capabilities of a small company will be different from that of a large company and recognize that we need a pre-certification program that accommodates both.

 

The initiative will begin immediately. Starting on August 1, companies can submit a statement of interest that includes the qualities listed above, requesting participation in the pilot to FDAPre-CertPilot@fda.hhs.gov. Then, during the month of August, FDA’s Digital Health Team will evaluate submissions and select companies that reflect the broad range of software developers. A critical component is that FDA will include small and large companies, traditional and non-traditional MedTech companies, and products that range in risk. This approach will create opportunities for more dynamic entrepreneurship and competition and help continue to drive product innovation.

 

FDA expects that the first four months of the pilot will better inform FDA’s regulatory team as well as product developers. FDA will hold a public workshop in January 2018 to report on and review the initial findings. The goal is to inform product developers who are not participating in the pilot, so they can understand our process and findings, to help better inform development programs underway outside of the pilot.

 

As FDA launches its Digital Health Innovation Action Plan, FDA is aware that apps and app updates come to market every day. But the most powerful feature of this market may not be one revolutionary app but rather a combination of apps that provides consumers and providers with the information they need. This can help people better manage their chronic diseases, which could result in less trips to the doctor for checkups, or better awareness of illness, like prompts to a parent with a sick child on when they need to see a provider.

 

FDA Approves New Treatment For Sickle Cell Disease

 

Sickle cell disease is an inherited blood disorder in which the red blood cells are abnormally shaped (in a crescent, or sickle, shape). This restricts the flow in blood vessels and limits oxygen delivery to the body’s tissues, leading to severe pain and organ damage. According to the National Institutes of Health, approximately 100,000 people in the United States have sickle cell disease. The disease occurs most often in African-Americans, Latinos and other minority groups. The average life expectancy for patients with sickle cell disease in the United States is approximately 40 to 60 years.

 

The FDA has approved Endari (L-glutamine oral powder) for patients age five years and older with sickle cell disease to reduce severe complications associated with this blood disorder. The safety and efficacy of Endari were studied in a randomized trial of patients ages 5-58 years old with sickle cell disease who had two or more painful crises within the 12 months prior to enrollment in the trial. Patients were assigned randomly to treatment with Endari or placebo, and the effect of treatment was evaluated over 48 weeks. Patients who were treated with Endari experienced fewer hospital visits for pain treated with a parenterally administered narcotic or ketorolac (sickle cell crises), on average, compared to patients who received a placebo (median 3 vs. median 4), fewer hospitalizations for sickle cell pain (median 2 vs. median 3), and fewer days in the hospital (median 6.5 days vs. median 11 days). Patients who received Endari also had fewer occurrences of acute chest syndrome (a life-threatening complication of sickle cell disease) compared with patients who received a placebo (8.6 percent vs. 23.1 percent). Common side effects of Endari include constipation, nausea, headache, abdominal pain, cough, pain in the extremities, back pain and chest pain.

 

Endari received Orphan Drug designation for this use, which provides incentives to assist and encourage the development of drugs for rare diseases. In addition, development of this drug was in part supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and/or effectiveness of products for use in rare diseases or conditions.

 

The FDA granted the approval of Endari to Emmaus Medical Inc.

 

FDA Unveils Plan to Eliminate Orphan Designation Backlog

 

For our last Orphan Drug Designation Request, FDA told us that there could be a 6 month review time. We did contact the Division and were told about the major backlog.

 

As authorized under the Orphan Drug Act, the Orphan Drug Designation Program provides orphan status to drugs and biologics that are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases, which are generally defined as diseases that affect fewer than 200,000 people in the United States. Orphan designation qualifies the sponsor of the drug for various development incentives, including tax credits for clinical trial costs, relief from prescription drug user fee if the indication is for a rare disease or condition, and eligibility for seven years of marketing exclusivity upon approval. A request for orphan designation is one step that can be taken in the drug development process and is different than the filing of a marketing application with the FDA.

 

The FDA has unveiled a strategic plan to eliminate the existing orphan designation request backlog and ensure continued timely response to all new requests for designation with firm deadlines. The agency’s Orphan Drug Modernization Plan comes a week after FDA Commissioner Scott Gottlieb committed to eliminating the backlog within 90 days and responding to all new requests for designation within 90 days of receipt during his testimony before a Senate subcommittee.

 

Currently, the FDA has about 200 orphan drug designation requests that are pending review. The number of orphan drug designation requests has steadily increased over the past five years. In 2016, the FDA’s Office of Orphan Products Development received 568 new requests for designation – more than double the number of requests received in 2012. The increased interest in the program is a positive development for those with rare diseases and under this new plan, the agency remains committed to advancing the program to ensure it can efficiently and adequately review these requests.

 

This is the first element of several efforts the FDA will undertake under its new “Medical Innovation Development Plan,“ which is aimed at ensuring that the FDA’s regulatory tools and policies are modern, risk based, and efficient. The goal of the plan is to seek ways the FDA can help facilitate the development of safe, effective and transformative medical innovations that have the potential to significantly impact disease and reduce overall health care costs. Among the elements of the plan to eliminate the backlog, the FDA will deploy a Backlog SWAT team comprised of senior, experienced reviewers with significant expertise in orphan drug designation. The team will focus solely on the backlogged applications, starting with the oldest requests. The agency will also employ a new streamlined Designation Review Template to increase consistency and efficiency of its reviews. The program will also look to collaborate within the agency’s medical product centers to create greater efficiency, including conducting joint reviews with the Office of Pediatric Therapeutics to review rare pediatric disease designation requests.

 

To ensure all future requests receive a response within 90 days of receipt, the agency will take a multifaceted approach. These efforts include, among other new steps: reorganizing the review staff to maximize expertise and improve workload efficiencies; better leveraging the expertise across the FDA’s medical product centers; and establishing a new FDA Orphan Products Council that will help address scientific and regulatory issues to ensure the agency is applying a consistent approach to regulating orphan drug products and reviewing designation requests.

 

The FDA intends to communicate around the successful elimination of the backlog by mid-September and will soon provide more information about the Medical Innovation Development Plan.

 

First Subcutaneous C1 Esterase Inhibitor to Treat Hereditary Angioedema (HAE)

 

Hereditary Angioedema (HAE), which is caused by having insufficient amounts of a plasma protein called C1-esterase inhibitor (or C1-INH), affects approximately 6,000 to 10,000 people in the U.S. People with HAE can develop rapid swelling of the hands, feet, limbs, face, intestinal tract or airway. These attacks of swelling can occur spontaneously, or can be triggered by stress, surgery or infection.

 

The FDA has approved Haegarda, the first C1 Esterase Inhibitor (Human) for subcutaneous (under the skin) administration to prevent HAE attacks in adolescent and adult patients. The subcutaneous route of administration allows for easier at-home self-injection by the patient or caregiver, once proper training is received.

 

Haegarda is a human plasma-derived, purified, pasteurized, lyophilized (freeze-dried) concentrate prepared from large pools of human plasma from U.S. donors. Haegarda is indicated for routine prophylaxis to prevent HAE attacks, but is not indicated for treatment of acute HAE attacks. The efficacy of Haegarda was demonstrated in a multicenter controlled clinical trial. The study included 90 subjects ranging in age from 12 to 72 years old with symptomatic HAE. Subjects were randomized to receive twice per week subcutaneous doses of either 40 IU/kg or 60 IU/kg, and the treatment effect was compared to a placebo treatment period. During the 16 week treatment period, patients in both treatment groups experienced a significantly reduced number of HAE attacks compared to their placebo treatment period.

 

The most common side effects included injection site reactions, hypersensitivity (allergic) reactions, nasopharyngitis (swelling of the nasal passages and throat) and dizziness. Haegarda should not be used in individuals who have experienced life-threatening hypersensitivity reactions, including anaphylaxis, to a C1-INH preparation or its inactive ingredients.

 

Haegarda received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs to treat rare diseases or conditions.

 

The FDA granted approval of Haegarda to CSL Behring LLC.

 

Fostering Medical Innovation: A Plan for Digital Health Devices

 

The following was reported by Scott Gottlieb, M.D., FDA Commissioner

 

Dr. Gottlieb indicated that it is incumbent upon FDA to ensure that they have the right policies in place to promote and encourage safe and effective innovation that can benefit consumers, and adopt regulatory approaches to enable the efficient development of these technologies. By taking an efficient, risk-based approach to regulations, FDA can promote health through the creation of more new and beneficial medical technologies. FDA can also help reduce the development costs for these innovations by making sure that our own policies and tools are modern and efficient, giving entrepreneurs more opportunities to develop products that can benefit people’s lives.

 

To this end, FDA will soon be putting forward a broad initiative that is focused on fostering new innovation across our medical product centers. However, today Dr. Gottlieb is focusing on one critical aspect of this innovation initiative: A new Digital Health Innovation Plan that is focused on fostering innovation at the intersection of medicine and digital health technology. This plan will include a novel, post-market approach to how FDA intends to regulate these digital medical devices.

 

According to one estimate, last year there were 165,000 health-related apps available for smartphones. Forecasts predict that such apps would be downloaded 1.7 billion times by 2017. From mobile apps and fitness trackers to clinical decision support software, innovative digital technologies have the power to transform health care in important ways, such as:

 

1. Empowering consumers to make more and better decisions every day about their own health, monitor and manage chronic health conditions, or connect with medical professionals, using consumer-directed apps and other technologies to help people live healthier lifestyles through fitness, nutrition, and wellness monitoring;

2. Enabling better and more efficient clinical practice and decision making through decision support software and technologies to assist in making diagnoses and developing treatment options; managing, storing, and sharing health records; and managing schedules and workflow;

3. Helping to address public health crises, such as the opioid epidemic that is devastating many American communities. In fact, FDA conducted a prize competition to encourage the development of a mobile app to help connect opioid users experiencing an overdose with nearby carriers of the prescription drug naloxone for emergency treatment.

 

For these and other digital technologies to take hold and reach their fullest potential, it is critical that FDA be forward-leaning in making sure that they have implemented the right policies and regulatory tools, and communicated them clearly.In this rapidly changing environment, ambiguity regarding how FDA will approach a new technology can lead innovators to invest their time and resources in other ventures. To encourage innovation, FDA should carry out its mission to protect and promote the public health through policies that are clear enough for developers to apply them on their own. Developers should not have to seek out, on a case-by-case basis, FDA’s position on every individual technological change or iterative software development.

 

Congress has already taken a major step to advance these goals in the 21st Century Cures Act. Expanding upon policies advanced by FDA’s Center for Devices and Radiological Health (CDRH), the Act revised FDA’s governing statute to, among other things, make clear that certain digital health technologies – such as clinical administrative support software and mobile apps that are intended only for maintaining or encouraging a healthy lifestyle – generally fall outside the scope of FDA regulation. Such technologies tend to pose low risk to patients but can provide great value to the health care system. FDA, led by CDRH, is working to implement the digital health provisions of the 21st Century Cures Act and, in the coming months, will be publishing guidance to further clarify what falls outside the scope of FDA regulation and to explain how the new statutory provisions affect pre-existing FDA policies. FDA will provide guidance to clarify their position on products that contain multiple software functions, where some fall outside the scope of FDA regulation, but others do not. In addition, FDA will provide new guidance on other technologies that, although not addressed in the 21st Century Cures Act, present low enough risks that FDA does not intend to subject them to certain pre-market regulatory requirements. Greater certainty regarding what types of digital health technology is subject to regulation and regarding FDA’s compliance policies will not only help foster innovation, but also will help the agency to devote more resources to higher risk priorities.

 

In addition to these efforts, FDA has announced a new initiative. This fall, as part of a comprehensive approach to the regulation of digital health tools and in collaboration with our customers, FDA will pilot an entirely new approach toward regulating this technology. This will be the cornerstone to a more efficient, risk-based regulatory framework for overseeing these medical technologies. While the pilot program is still being developed, FDA is considering whether and how, under current authorities, they can create a third party certification program. Under this program, lower risk digital health products could be marketed without FDA premarket review and higher risk products could be marketed with a streamlined FDA premarket review. Certification could be used to assess, for example, whether a company consistently and reliably engages in high quality software design and testing (validation) and ongoing maintenance of its software products. Employing a unique pre-certification program for software as a medical device (SaMD) could reduce the time and cost of market entry for digital health technologies.

 

In addition, post-market collection of real-world data might be able to be used to support new and evolving product functions. For example, product developers could leverage real-world data gathered through the National Evaluation System for health Technology (NEST) to expedite market entry and subsequent expansion of indications more efficiently. NEST will be a federated virtual system for evidence generation composed of strategic alliances among data sources including registries, electronic health records, payer claims, and other sources. The Medical Device Innovation Consortium (MDIC), a 501(c)(3) public-private partnership, is serving as an independent coordinating center that operates NEST. In the coming weeks, MDIC will announce the establishment of a Governing Committee for the NEST Coordinating Center comprised of stakeholder representatives of the ecosystem, such as patients, health care professionals, health care organizations, payers, industry, and government. Although FDA does not own or operate NEST, they have been establishing strategic alliances among data sources to accelerate NEST’s launch with the initial version of a fully operational system anticipated by the end of 2019. Applying this firm-based approach, rather than the traditional product-based approach, combined with leveraging real-world evidence, would create market incentives for greater investment in and growth of the digital health technology industry. Such processes could enable developers to deploy new or updated software more rapidly and would help FDA to better focus its resources.

 

Through these and other steps, according to Dr. Gottlieb, FDA will help innovators navigate a new, modern regulatory process so that promising, safe and effective developments in digital health can advance more quickly and responsibly, and Americans can reap the full benefits from these innovations. These efforts are just one part of a much broader initiative that FDA is currently undertaking to advance policies that promote the development of safe and effective medical technologies that can help consumers improve their health. FDA’s goal is to make sure that FDA has the most modern and efficient regulatory approaches when it comes to evaluating new, beneficial technologies. Scott Gottlieb, M.D., is Commissioner of the U.S. Food and Drug Administration

 

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