FDA Expands Approval of Imfinzi to Reduce the Risk of Progressing NSCLC

 

Lung cancer is the leading cause of cancer death in the United States, with an estimated 222,500 new diagnoses and 155,870 deaths in 2017, according to the National Cancer Institute at the National Institutes of Health. The most common type of lung cancer, non-small cell lung cancer (NSCLC), occurs when cancer cells form in the tissues of the lung. Stage III NSCLC means tumors have spread to nearby lymph nodes or into other parts of the body near the lungs.

 

The FDA has approved Imfinzi (durvalumab) for the treatment of patients with stage III (NSCLC whose tumors are not able to be surgically removed (unresectable) and whose cancer has not progressed after treatment with chemotherapy and radiation (chemoradiation). According to FDA, this is the first treatment approved for stage III unresectable NSCLC to reduce the risk of the cancer progressing, when the cancer has not worsened after chemoradiation. For patients with stage III lung cancer that cannot be removed surgically, the current approach to prevent progression is chemoradiation. Although a small number of patients may be cured with the chemoradiation, the cancer may eventually progress. Patients now have an approved therapy that has been shown to keep the cancer from progressing for a longer time after chemoradiation.

 

Imfinzi targets the PD-1/PD-L1 pathway (proteins found on the body’s immune cells and some cancer cells). By blocking these interactions, Imfinzi may help the body’s immune system attack cancer cells. Imfinzi was previously granted accelerated approval in 2017 for the treatment of certain patients with locally advanced or metastatic bladder cancer. The approval of Imfinzi for the treatment of stage III, unresectable NSCLC was based on a randomized trial of 713 patients whose cancer had not progressed after completing chemotherapy and radiation. The trial measured the length of time the tumors did not have significant growth after starting treatment with Imfinzi or a placebo (progression-free survival). The median progression-free survival for patients taking Imfinzi was 16.8 months compared to 5.6 months for patients receiving a placebo. In addition, the sponsor has agreed to a post-marketing commitment to provide additional information from their study to the FDA about how long patients lived following treatment with Imfinzi after chemotherapy and radiation (overall survival).

 

Common side effects of Imfinzi in patients with stage III unresectable NSCLC include cough, fatigue, inflammation in the lungs (pneumonitis/radiation pneumonitis), upper respiratory tract infections, difficulty breathing and rash. Serious risks of Imfinzi include immune-mediated side effects, where the body’s immune system attacks healthy cells or organs, such as the lungs (pneumonitis), liver (hepatitis), colon (colitis), hormone-producing glands (endocrinopathies) and kidneys (nephritis). Other serious side effects of Imfinzi include infection and infusion-related reactions. Imfinzi can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception.

 

The FDA granted this application Priority Review and Breakthrough Therapy designations. Imfinzi is marketed by AstraZeneca.

 

New Treatment for Certain Digestive Tract Cancers

 

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) can be present in the pancreas and in different parts of the gastrointestinal tract such as the stomach, intestines, colon and rectum. It is estimated that approximately one out of 27,000 people are diagnosed with GEP-NETs per year.

 

The FDA has approved Lutathera (lutetium Lu 177 dotatate) for the treatment adult patients with somatostatin receptor-positive GEP-NETs. Lutathera is a radioactive drug that works by binding to a part of a cell called a somatostatin receptor, which may be present on certain tumors. After binding to the receptor, the drug enters the cell allowing radiation to cause damage to the tumor cells. This is the first time a radioactive drug, or radiopharmaceutical, has been approved for the treatment of GEP-NETs.

 

The approval of Lutathera was supported by two studies. The first was a randomized clinical trial in 229 patients with a certain type of advanced somatostatin receptor-positive GEP-NET. Patients in the trial either received Lutathera in combination with the drug octreotide or octreotide alone. The study measured the length of time the tumors did not grow after treatment (progression-free survival). Progression-free survival was longer for patients taking Lutathera with octreotide compared to patients who received octreotide alone. This means the risk of tumor growth or patient death was lower for patients who received Lutathera with octreotide compared to that of patients who received only octreotide.

 

The second study was based on data from 1,214 patients with somatostatin receptor-positive tumors, including GEP-NETS, who received Lutathera at a single site in the Netherlands. Complete or partial tumor shrinkage was reported in 16% of a subset of 360 patients with GEP-NETs who were evaluated for response by the FDA. Patients initially enrolled in the study received Lutathera as part of an expanded access program. Expanded access is a way for patients with serious or immediately life-threatening diseases or conditions who lack therapeutic alternatives to gain access to investigational drugs for treatment use.

 

Common side effects of Lutathera include low levels of white blood cells (lymphopenia), high levels of enzymes in certain organs (increased GGT, AST and/or ALT), vomiting, nausea, high levels of blood sugar (hyperglycemia) and low levels of potassium in the blood (hypokalemia). Serious side effects of Lutathera include low levels of blood cells (myelosuppression), development of certain blood or bone marrow cancers (secondary myelodysplastic syndrome and leukemia), kidney damage (renal toxicity), liver damage (hepatotoxicity), abnormal levels of hormones in the body (neuroendocrine hormonal crises) and infertility. Lutathera can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception. Patients taking Lutathera are exposed to radiation. Exposure of other patients, medical personnel, and household members should be limited in accordance with radiation safety practices.

 

Lutathera was granted Priority Review, under which the FDA’s goal is to take action on an application within six monthswhere the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition. Lutathera also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

 

The FDA granted the approval of Lutathera to Advanced Accelerator Applications.

FDA Collaborates with Department of Defense

 

The U.S. Food and Drug Administration (FDA) and the Department of Defense’s (DoD) Office of Health Affairs announced today the launch of a joint program to prioritize the efficient development of safe and effective medical products intended to save the lives of American military personnel.

 

The framework for the program was put in place through H.R.4374, which authorized DoD to request, and the FDA to provide, assistance to expedite development and the FDA’s review of products to diagnose, treat, or prevent serious or life-threatening diseases or conditions facing American military personnel. Utilizing this law’s expanded authorities, the FDA will work closely with Health Affairs to better understand the military’s medical needs for deployed personnel; give the highest level of attention to and expedite its review of priority DoD medical products in a manner similar to products under the breakthrough designation program; provide ongoing technical advice to Health Affairs to aid in the rapid development and manufacturing of medical products for use by the military; and, take a closer look at products currently under development to determine opportunities to expedite their availability.

 

The FDA outlined its approach in an initial work plan the agency developed in close collaboration with DoD. This was done in accordance with H.R.4374, which was enacted in December 2017 along with the National Defense Authorization Act for fiscal year 2018. Because current high-priority DoD product programs include freeze-dried plasma, cold-stored platelets, and cryopreserved platelets, the initial phase of the program will be conducted among the FDA’s Center for Biologics Evaluation and Research (CBER) and Health Affairs. Leadership from the FDA’s CBER will meet with Health Affairs on a regular basis as part of this program, which will help the FDA’s experts efficiently prioritize and expedite availability of biological products that are essential to the urgent care of those involved in national defense.

 

As part of this program, the FDA and Health Affairs will hold one or more workshops in 2018 to discuss aspects of the scientific and clinical development of products that are important to the health of military personnel. Findings from this workshop will inform an FDA guidance document that will help commercial product developers identify opportunities to fulfill unmet medical needs for battlefield settings and other front-line conditions experienced by men and women of the U.S. armed forces.

 

While the availability of certain biological products is of the upmost priority, the FDA and Health Affairs recognize that there is need for a broad range of medical products for service members, including preventive vaccines and therapeutics, and that these needs will continue to evolve in the future. Accordingly, the program is just the initial step in building an ongoing partnership between these two federal partners that can extend across the FDA’s capabilities.

 

First Treatment for Breast Cancer with a Certain Inherited Mutation

 

Breast cancer is the most common form of cancer in the United States. The National Cancer Institute at the National Institutes of Health estimates approximately 252,710 women will be diagnosed with breast cancer this year, and 40,610 will die of the disease. Approximately 20-25% of patients with hereditary breast cancers and 5-10% of patients with any type of breast cancer have a BRCA mutation. BRCA genes are involved with repairing damaged DNA and normally work to prevent tumor development. However, mutations of these genes may lead to certain cancers, including breast cancers.

 

The FDA has expanded the approved use of Lynparza (olaparib tablets) to include the treatment of patients with certain types of breast cancer that have spread (metastasized) and whose tumors have a specific inherited (germline) genetic mutation BRACAnalysis CDx. This is the first PARP (poly ADP-ribose polymerase) inhibitor approved to treat breast cancer, and it is the first time any drug has been approved to treat certain patients with metastatic breast cancer who have a “BRCA“ gene mutation.

 

Lynparza is a PARP inhibitor that blocks an enzyme involved in repairing damaged DNA. By blocking this enzyme, DNA inside the cancerous cells with damaged BRCA genes may be less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth. Lynparza was first approved by the FDA in 2014 to treat certain patients with ovarian cancer and is now indicated for the treatment of patients with germline breast cancer susceptibility gene (BRCA) mutated, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer, who have been previously treated with chemotherapy. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior hormonal (endocrine) therapy or be considered inappropriate for endocrine treatment.

 

The FDA has also expanded the approval of the BRACAnalysis CDx, an approved companion diagnostic to Lynparza, to include the detection of BRCA mutations in blood samples from patients with breast cancer.

 

The safety and efficacy of Lynparza for the treatment of breast cancer was based on a randomized clinical trial of 302 patients with HER2-negative metastatic breast cancer with a germline BRCA mutation. The trial measured the length of time the tumors did not have significant growth after treatment (progression-free survival). The median progression-free survival for patients taking Lynparza was 7 months compared to 4.2 months for patients taking chemotherapy only. Common side effects of Lynparza include low levels of red blood cells (anemia), low levels of certain white blood cells (neutropenia, leukopenia), nausea, fatigue, vomiting, common cold (nasopharyngitis), respiratory tract infection, influenza, diarrhea, joint pain (arthralgia/myalgia), unusual taste sensation (dysgeusia), headache, indigestion (dyspepsia), decreased appetite, constipation and inflammation and sores in the mouth (stomatitis). Severe side effects of Lynparza include development of certain blood or bone marrow cancers (myelodysplastic syndrome/acute myeloid leukemia) and inflammation in the lungs (pneumonitis). Lynparza can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception. Women taking Lynparza should not breastfeed as it could cause harm to a newborn baby.

 

This application was granted Priority Review, under which the FDA’s goal is to take action on an application within 6 months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition. Lynparza is also approved for the treatment of patients with BRCA-mutated, advanced ovarian cancer who have received three or more treatments of chemotherapy, and for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer whose tumors have completely or partially responded to chemotherapy.

 

The FDA granted the approval of Lynparza to AstraZeneca Pharmaceuticals LP. The approval of the BRACAnalysis CDx was granted to Myriad Genetic Laboratories, Inc.

 

New Patient Engagement Collaborative

 

The following was excerpted from FDA Voice, posted December 20, 2017 by By: Nina L. Hunter, Ph.D., and Rachel E. Sherman, M.D, M.P.H.

 

According to FDA Voice, the FDA is committed to collaborating with patients, caregivers, and advocates, as well as incorporating the various perspectives from these groups into the FDA’s regulatory decision-making processes. In fact, members of the patient and stakeholder communities commented in public feedback on Section 1137, Patient Participation in Medical Product Discussions, of the Food and Drug Administration Safety and Innovation Act (FDASIA). Stakeholders recommended that the FDA create an outside group to provide input on patient engagement across the agency. FDA has announced that in response to that feedback and to accelerate the FDA’s efforts in this area, it has published a request for nominations to join the FDA’s Patient Engagement Collaborative (PEC). The PEC will be coordinated by the FDA and the public-private partnership, the Clinical Trials Transformation Initiative. FDA is seeking a group of diverse representatives from the patient community to participate in the PEC including:

 

1. Patients who have personal disease experience

2. Caregivers who support patients, such as a parent, child, partner, other family member, or friend, and who have personal disease experience through this caregiver role

3. Representatives from patient groups who, through their role in the patient group, have direct or indirect disease experience

 

The PEC will provide an ongoing forum to discuss how to achieve more meaningful patient engagement in medical product development and other regulatory discussions. Topics to be discussed may include making patient engagement more systematic; how to improve transparency, education and communication; new strategies for enhancing patient engagement; and new models for patients to collaborate as partners in the medical product development and FDA review process. The PEC builds on the agency’s existing patient engagement efforts, such as the Patient Focused Drug Development meetings (for drugs and biologic products) and the Patient Preference Initiative (for medical devices).

 

The new collaborative will be modeled after the European Medicines Agency’s Patients’ and Consumers’ Working Party (PCWP) which “has enabled the Agency to build upon its existing interactions with patients and consumers.“ Examples of PCWP accomplishments include having patients review information on medicines ahead of publication to ensure that the information is “clear and relevant,“ deciding on the eligibility criteria for patient and consumer groups who will be working with EMA, and involving patients as experts in EMA regulatory activities. The PEC will be spearheaded by the FDA’s new Patient Affairs Staff (PAS) in the Office of Medical Products and Tobacco (OMPT), which is responsible for the coordination of agency-wide and cross-center projects related to patient engagement. The PAS will work closely with the medical product centers, the Office of External Affairs (OEA), and other offices across the agency to complement and support ongoing patient engagement efforts. Specifically, the PAS will focus on the following key areas:

 

1. Creating and assisting with public and private collaborations and partnerships with external groups of patients to discuss topics around medical product development and regulatory policies

2. Coordinating cross-cutting programs and activities to leverage best practices and enhance patient engagement

3. Facilitating consistent cross-center policy-making and common standards to enhance integration of patient perspectives into the regulatory and scientific process

4. Building a framework for hosting and maintaining a shared database of patient engagement information

5. Providing navigation services to triage inquiries from patients and patient organizations

6. Establishing a centralized point of entry into the FDA for patients and their advocates (existing FDA interactions will not be affected)

7. Enhancing our external communication platform to create awareness of the FDA’s patient engagement activities and regulatory processes

 

This new Collaborative is also facilitated by provisions in both the 21st Century Cures Act of 2016 and the Food and Drug Administration Reauthorization Act of 2017. Both sought to foster patient participation and incorporate patient experiences in the regulatory process. The goal of the nomination process announced today is to identify individuals interested in serving as members of the PEC.

 

Once-Monthly Buprenorphine Injection for Opioid Use Disorder

 

Improving access to prevention, treatment and recovery services, including the full range of medication-assisted treatments (MAT), is a focus of the FDA’s ongoing work to reduce the scope of the opioid crisis and one part of the U.S. Department of Health and Human Services’ Five-Point Strategy to Combat the Opioid Crisis. Opioid use disorder (OUD) is the diagnostic term used for a chronic neurobiological disease characterized by a problematic pattern of opioid use leading to significant impairment or distress. OUD includes signs and symptoms that reflect compulsive, prolonged self-administration of opioid substances for no legitimate medical purpose or, if another medical condition is present that requires opioid treatment, the opioid is used in doses far greater than the amount needed for treatment of that medical condition. MAT is a comprehensive approach that combines approved medications (currently, methadone, buprenorphine or naltrexone) with counseling and other behavioral therapies to treat patients with OUD. Regular adherence to MAT with buprenorphine reduces opioid withdrawal symptoms and the desire to use opioids, without causing the cycle of highs and lows associated with opioid misuse or abuse. At proper doses, buprenorphine also decreases the pleasurable effects of other opioids, making continued opioid abuse less attractive. According to the Substance Abuse and Mental Health Services Administration, patients receiving MAT for their OUD cut their risk of death from all causes in half.

 

Buprenorphine for the treatment of moderate-to-severe OUD is currently approved as a tablet, as an implant, or a sublingual film (absorbed under the tongue) that dissolves in the mouth. The FDA has recently approved Sublocade, the first once-monthly injectable buprenorphine product for the treatment OUD in adult patients who have initiated treatment with a transmucosal (absorbed through mucus membrane) buprenorphine-containing product. It is indicated for patients that have been on a stable dose of buprenorphine treatment for a minimum of seven days. Sublocade provides a new treatment option for patients in recovery who may value the benefits of a once-monthly injection compared to other forms of buprenorphine, such as reducing the burden of taking medication daily as prescribed (medical adherence). An independent FDA advisory committee supported the approval of Sublocade.

 

Sublocade should be used as part of a complete treatment program that includes counseling and psychosocial support. Sublocade is a drug-device combination product that utilizes buprenorphine and the Atrigel Delivery System in a pre-filled syringe. It is injected by a health care professional (HCP) under the skin (subcutaneously) as a solution, and the delivery system forms a solid deposit, or depot, containing buprenorphine. After initial formation of the depot, buprenorphine is released by the breakdown (biodegradation) of the depot. In clinical trials, Sublocade provided sustained therapeutic plasma levels of buprenorphine over the one-month dosing interval.

 

The safety and efficacy of Sublocade were evaluated in two clinical studies (one randomized controlled clinical trial and one open-label clinical trial) of 848 adults with a diagnosis of moderate-to-severe OUD who began treatment with buprenorphine/naloxone sublingual film. Once the dose was determined stable, patients were given Sublocade by injection. A response to MAT was measured by urine drug screening and self-reporting of illicit opioid use during the six-month treatment period. Results indicated that Sublocade-treated patients had more weeks without positive urine tests or self-reports of opioid use, and a higher proportion of patients had no evidence of illicit opioid use throughout the treatment period, compared to the placebo group. The most common side effects from treatment with Sublocade include constipation, nausea, vomiting, headache, drowsiness, injection site pain, itching (pruritus) at the injection site and abnormal liver function tests. The safety and efficacy of Sublocade have not been established in children or adolescents less than 17 years of age. Clinical studies of Sublocade did not include participants over the age of 65.

 

The FDA is requiring postmarketing studies to assess which patients would benefit from a higher dosing regimen, to determine whether Sublocade can be safely initiated without a dose stabilization period of sublingual buprenorphine, to assess the feasibility of administering Sublocade at a longer inter-dose interval than once-monthly and to determine a process for transitioning patients with long-term stability on a transmucosal buprenorphine dose to a monthly dose of Sublocade without the use of a higher dose for the first two months of treatment (loading dose). Sublocade has a boxed warning that provides important safety information, including the risks of intravenous self-administration. If the product were to be administered intravenously rather than subcutaneously, the solid mass could cause occlusion (blockage), tissue damage or embolus (solid material that is carried in the blood and can become lodged in a blood vessel, which can lead to death). Sublocade must be prescribed and dispensed as part of a Risk Evaluation and Mitigation Strategy (REMS) to ensure that the product is not distributed directly to patients. Sublocade will be provided to HCPs through a restricted program, administered only by HCPs in a health care setting, and will require health care settings and pharmacies that dispense Sublocade to complete an enrollment form attesting that they have procedures in place to ensure that Sublocade is dispensed only to HCPs and not directly to patients.

 

The FDA granted approval of Sublocade to Indivior Inc. and the application had Priority Review and Fast Trackdesignations.

 

Puerto Rico Related Medical Product Shortages

 

According to FDA, while Puerto Rico is making progress in its effort to recover from the devastation left by the hurricanes, it remains a long process and there’s a lot of work left to do. At the FDA, is remaining vigilant about helping address the challenges that remain. Power is being restored across the island and, importantly, some major medical product manufacturing facilities are coming back online and stabilizing their production. However, until the grid is reliably restored, many firms will continue to run on generator power or require generators as a backup and production levels will not return to their baseline levels.

 

Over the last few weeks, FDA has been addressing the IV saline products shortage, which was exacerbated by Hurricane Maria. FDA has been closely working with one supplier, Baxter, to help them restore production operations in their Puerto Rico facilities. FDA also approved IV solution products from Fresenius Kabi and Laboratorios Grifols to mitigate the shortage, and both of those companies have been working to increase production of saline products. Thanks to steps like these, FDA now believes that the shortage situation related to IV saline products will improve by the end of 2017. While FDA has made progress on this front, unfortunately there continue to be drug shortage issues that are of serious concern to the agency. In addition to FDA’s ongoing concerns related to IV saline products, FDA is also are particularly focused on the shortage of amino acids for injection. This product is of critical need for patients, including children and infants, who are not able to eat and need to receive their nutrition intravenously. Like with saline, an ongoing amino acid short supply situation was worsened by Hurricane Maria’s impact on Puerto Rican drug manufacturing facilities that manufacture this product.

 

Most notably, the hurricane disrupted Baxter’s amino acids production facilities in Puerto Rico; Baxter is one of the largest manufacturers of this product serving the U.S. market. In order to help mitigate this shortage, the FDA has worked with Baxter to facilitate the temporary importation of amino acids for pediatric and adult formulations of IV amino acids from Baxter facilities in the United Kingdom and Italy. FDA is also working with other manufacturers of amino acids to increase supplies to address the shortage, including ICU Medical and B. Braun. ICU Medical had experienced manufacturing delays, but now plans to return to the market soon, which will further help address the shortage. FDA continues to work closely with federal and Puerto Rican authorities to address the needs of manufacturers on the island for power and other resources. These efforts have been focused on the needs of patients — to prevent potential shortages of medically important products where possible, and help ensure that any shortages that do occur are mitigated as quickly as possible. FDA does understand the burden and stress drug shortages have on patients, health care providers and hospitals. FDA is monitoring approximately 90 medical products manufactured on Puerto Rico (which includes biologics, devices and drugs) that are important to patients. Mitigating medical product shortages will require a sustained effort by industry, the agency and other partners as we work with manufacturers to return to production levels that adequately meet the needs of patients.

 

FDA Launches Comprehensive Regenerative Medicine Policy Framework

 

The FDA has announced a comprehensive policy framework for the development and oversight of regenerative medicine products, including novel cellular therapies. The framework, which is outlined in a suite of four guidance documents, builds upon the FDA’s existing risk-based regulatory approach to more clearly describe what products are regulated as drugs, devices, and/or biological products. Further, two of the guidance documents propose an efficient, science-based process for helping to ensure the safety and effectiveness of these therapies, while supporting development in this area. The suite of guidance documents also defines a risk-based framework for how the FDA intends to focus its enforcement actions against those products that raise potential significant safety concerns. This proposed framework is intended to balance the agency’s commitment to safety with mechanisms to drive further advances in regenerative medicine so innovators can bring new, effective therapies to patients as quickly and safely as possible. The policy also delivers on important provisions of the 21st Century Cures Act.

 

The framework includes two final guidance documents and two draft guidance documents.

 

New Final Guidance Documents

 

The two final guidance documents clarify the FDA’s interpretation of the risk-based criteria manufacturers use to determine whether a product is subject to the FDA’s premarket review. The first guidance provides greater clarity around when cell and tissue-based products would be excepted from the established regulations if they are removed from and implanted into the same individual within the same surgical procedure and remain in their original form. The second final guidance helps stakeholders better understand how existing regulatory criteria apply to their products by clarifying how the agency interprets the existing regulatory definitions “minimal manipulation“ and “homologous use.“

 

As this field advances, the FDA has noted that there are a growing number of regenerative medicine products subject to FDA premarket authorization. These guidance documents will help explain how the FDA will provide a risk-based framework for its oversight. The policy framework defines how we intend to take action against unsafe products while facilitating continued innovation of promising technologies. To accomplish this goal, the guidance document has clarified the FDA’s view of “minimal manipulation“ and “homologous use.“ These are two concepts that are defined in current regulation to establish the legal threshold for when a product is subject to the FDA’s premarket approval requirements. By further clarifying these terms in the final guidance, the FDA is applying a modern framework for its oversight. Under the new policy, in order to allow manufacturers of products time to comply with the requirements, for the first 36 months following issuance of the final guidance document the FDA intends to exercise enforcement discretion for certain products that are subject to the FDA’s premarket review under the existing regulations, but are not currently meeting these requirements. The FDA does not intend to exercise such enforcement discretion for those products that pose a potential significant safety concern. Going forward, the FDA will apply a risk-based approach to enforcement, taking into account how products are being administered as well as the diseases and conditions for which they are being used. This risk-based approach allows product manufacturers time to engage with the FDA, as to determine if they need to submit a marketing authorization application and, if so, submit their application to the FDA for approval.

 

New Draft Guidance Documents

 

The two draft guidances provide important information to help spur development and access to innovative regenerative therapies. The first draft guidance, which builds off the regenerative medicine provisions in the 21st Century Cures Act, addresses how the FDA intends to simplify and streamline its application of the regulatory requirements for devices used in the recovery, isolation, and delivery of regenerative medicine advanced therapies (RMATs), including combination products. The guidance specifies that devices intended for use with a specific RMAT may, together with the RMAT, be considered to comprise a combination product.

 

The second draft guidance describes the expedited programs that may be available to sponsors of regenerative medicine therapies, including the new Regenerative Medicine Advanced Therapy (RMAT) designation created by the 21st Century Cures Act, Priority Review, and Accelerated Approval. In addition, the guidance describes the regenerative medicine therapies that may be eligible for RMAT designation – including cell therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products, as well as gene therapies that lead to a durable modification of cells or tissues (including genetically modified cells).

 

Both draft guidance documents will have 90-day comment periods.

 

First Treatment Approved for Certain Patients with Erdheim-Chester Disease

 

Erdheim-Chester Disease (ECD) is a slow-growing blood cancer that originates in the bone marrow, and causes an increased production of histiocytes, a type of white blood cell. Excess histiocytes can result in tumors infiltrating many organs and tissues throughout the body, including the heart, lungs, brain and others. ECD is estimated to affect 600 to 700 patients worldwide. Approximately 54% of patients with ECD have the BRAF V600 mutation. Patients with ECD also have very limited life expectancies.

 

The FDA has expanded the approval of Zelboraf (vemurafenib) to include the treatment of certain adult patients with ECD. Zelboraf is indicated to treat patients whose cancer cells have the BRAF V600 mutation. This product was first approved in 2011 to treat certain patients with melanoma that harbor the BRAF V600E mutation. This is the first FDA-approved treatment for ECD.

 

Zelboraf is a kinase inhibitor that works by blocking certain enzymes that promote cell growth. The efficacy of Zelboraf for the treatment of ECD was studied in 22 patients with BRAF-V600-mutation positive ECD. The trial measured the percent of patients who experienced a complete or partial reduction in tumor size (overall response rate). In the trial, 11 patients (50%) experienced a partial response and 1 patient (4.5%) experienced a complete response. Common side effects of Zelboraf in patients with ECD include joint pain (arthralgia); small, raised bumps (maculo-papular rash); hair loss (alopecia); fatigue; change in the heart’s electrical activity (prolonged QT interval) and skin growths (papilloma). Severe side effects of Zelboraf include the development of new cancers (skin cancer, squamous cell carcinoma or other cancers), growth of tumors in patients with BRAF wild-type melanoma, hypersensitivity reactions (anaphylaxis and DRESS syndrome), severe skin reactions (Stevens-Johnson Syndrome and toxic epidermal necrolysis), heart abnormalities (QT prolongation), liver damage (hepatotoxicity), photosensitivity, severe reactions in the eye (uveitis), immune reactions after receiving radiation treatment (radiation sensitization and radiation recall), kidney failure and thickening of tissue in the hands and feet (Dupuytren’s contracture and plantar fascial fibromatosis). Zelboraf can also cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception.

 

The FDA granted this application Priority Review and Breakthrough Therapy designations for this indication. Zelboraf 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 Zelboraf to Hoffman-LaRoche, Inc.

 

Mutual Recognition of Manufacturing Facilities

 

Some drugs approved in the U.S. are either fully manufactured overseas or made in the U.S. but contain some foreign ingredients. All drugs approved in the U.S., regardless of where they are made, must comply with applicable U.S. regulations. One way the FDA oversees drug manufacturing is by routinely inspecting domestic and foreign drug manufacturing plants for compliance with manufacturing standards that assure quality and product label requirements.

 

The FDA has determined that it will recognize eight European drug regulatory authorities as capable of conducting inspections of manufacturing facilities that meet FDA requirements. The eight regulatory authorities found to be capable are those located in: Austria, Croatia, France, Italy, Malta, Spain, Sweden and the United Kingdom. This achievement marks an important milestone to successful implementation and operationalization of the amended Pharmaceutical Annex to the 1998 U.S.-European Union (EU) Mutual Recognition Agreement (MRA) that enables U.S. and EU regulators to utilize each other’s good manufacturing practice inspections of pharmaceutical manufacturing facilities.

 

According to FDA, beginning November 1, it will take the unprecedented and significant step forward in realizing the key benefits of the Mutual Recognition Agreement with its European counterparts in that FDA will now rely on the inspectional data obtained by these eight regulatory agencies. FDA added that the progress made so far puts it on track to meet our goal of completing all 28 capability assessments in the EU by July 2019.

 

In June 2017, the European Commission determined that the FDA “has the capability, capacity and procedures in place to carry out GMP inspections at a level equivalent to the EU.“ The completion of these capability assessments enables the FDA and the EU to avoid duplication of drug inspections and allows regulators to devote more resources to other manufacturing facilities in countries where there may be greater risk. Ultimately, this prioritization of inspections will help identify potential drug quality problems more quickly and prevent poor quality drugs from entering the U.S. market.

 

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