Expanded Access: FDA Describes Efforts to Ease Application Process

 

The following was extracted from FDA Voice and posted on October 3, 2017.

 

FDA has a long history of supporting patient access to investigational new treatments. This includes working with drug and device companies through the clinical trial process that may lead to FDA approval of the treatment. FDA also offer expanded access programs that provide investigational drugs and devices to patients with serious conditions (generally prior to product approval), when there is no therapeutic alternative.

 

Each year, FDA receives over 1,000 applications for the treatment of patients through expanded access, also known as compassionate use, and the agency authorizes the vast majority (about 99%). FDA recognizes that time is critical for these seriously ill patients who do not have alternative therapies, and who cannot take part in a clinical trial of an investigational therapy. Submissions are usually authorized quickly, often in a matter of days. In the case of emergencies, FDA will typically provide authorization over the phone in a matter of hours. In an effort to eliminate potential hurdles that might delay or even discourage applications, FDA streamlined the expanded access process by introducing a new application form which a physician may use to request expanded access for their patient. Form FDA 3926 reduced the number of required information fields and attachments, and is estimated to take only 45 minutes for a physician to complete. Before expanded access can occur, the drug company must decide whether or not to provide the product. FDA cannot require a manufacturer to provide a product.

 

FDA is lifting another potential burden for physicians who apply to FDA to use an investigational drug to treat their patient. Prior to treating a patient under expanded access, the physician must obtain approval from the Institutional Review Board (IRB) at their facility. This is an important step to protect the rights, safety and well-being of human subjects in clinical research – but assembling the full board may cause delays because it may not routinely meet. As part of a plan to simplify the process for physicians seeking access to an investigational product to treat their patient, FDA has announced that just one IRB member – the chair or another appropriate person – can now approve the treatment. Dr. Gottlieb, FDA Commissioner, believes the simplified IRB process will facilitate access while still protecting patients.

 

More simplifications and clarifications are also in the pipeline. FDA has seen some reluctance among companies to provide investigational drugs for expanded access. This may have been due, in part, to uncertainty about how data for adverse events that occur during treatment under expanded access are viewed by FDA. Companies have voiced concerns that any apparent negative effects might jeopardize the product’s development. FDA recognizes that patients receiving expanded access are usually treated outside of a controlled clinical trial setting. As a result, they may have more advanced disease than clinical trial participants, be receiving other drugs at the same time, and have other diseases. FDA recognizes that these factors make it more difficult to determine the cause an adverse reaction. To clarify how adverse event data in these circumstances are viewed, FDA has updated the guidance for industry entitled, ?Expanded Access to Investigational Drugs for Treatment Use: Questions and Answers’ (questions 25 and 26). The guidance clarifies that suspected adverse reactions must be reported “only if there is evidence to suggest a causal relationship between the drug and the adverse event.“ Dr. Gottlieb is confident these changes will help to address recent issues raised by the Government Accountability Office (GAO), which said that FDA “should further clarify how adverse event data are used.“ FDA is still evaluating the GAO recommendations to identify other possible ways to respond to their concerns.

 

FDA is committed to helping patients and physicians fully understand the expanded access process. Dedicated staff in the Office of Health and Constituent Affairs and CDER’s Office of Communications, Division of Drug Information, already assist physicians and patients in navigating this system. FDA issued three final guidance documents last year to clarify and explain the process. This past July, FDA collaborated with the Reagan-Udall Foundation, patient advocacy groups, the pharmaceutical industry, and other federal agencies to launch a new online tool called the Expanded Access Navigator. This includes a directory where companies can submit public links to their expanded access policies, the criteria used by companies to determine whether to make a drug available through expanded access, and contact information. The directory offers patients and physicians a helpful starting point for researching available investigational therapies. In addition, FDA is working with the Reagan-Udall Foundation to expand this new tool. FDA is pleased to announce that Reagan-Udall will expand its portfolio to include FDA’s Rare Disease Program, with the goal of promoting more expanded access to treatments for rare disorders.

 

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.

 

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