FDA Brief, Weeks of Nov. 9th and Nov. 16th, 2015

  • FDA Voice

The Case for Quality: Working with Stakeholders to Improve the Safety of Medical Devices for Patients

By: Howard Sklamberg, J.D., Jeffrey Shuren, M.D., J.D., and Melinda K. Plaisier, M.S.W.

Case for Quality (CfQ) : To identify and promote practices that will result in higher quality devices. 3 priorities:

Focus on Quality. Present in day-to-day device design and production, identify characteristics that are critical to the quality of a particular device. Shared understanding of product features and manufacturing processes most important to patient safety.

Stakeholder engagement. Collaborate and solicit feedback.

Data transparency.. Device data ( including recalls and adverse event reports) at open.fda.gov.

Expected Outcome : Allow stakeholders to focus resources on activities with the greatest impact on assuring that patients and users receive high-quality devices.


Continue reading “FDA Brief, Weeks of Nov. 9th and Nov. 16th, 2015”

CDRH Workshops, CDER Botanical Drug Review

CDRH Industry Basics Workshop – Purchasing Controls & Process Validation – November 4, 2015

Learning Objectives:

  • Understand the Intent and Background of Purchasing Controls
  • Define Product, Component and Service
  • Understand Purchasing Controls Requirements, Voluntary Guidance and Best Practices
  • Recognize the Links between Purchasing Controls and other Quality System (QS) requirements such as Design Controls and Acceptance Activities



CDRH  Public Workshop – In Vitro Diagnostic Testing for Direct Oral Anticoagulants, October 26, 2015

Learning Objectives


CDRH Public Workshop – Standards Based Approach to Analytical Performance Evaluation of Next Generation Sequencing In Vitro Diagnostic Tests, November 12, 2015

Learning Objectives: Optimize FDA’s regulation of next-generation sequencing (NGS)-based in vitro diagnostic tests

  • Analytical standards and approaches to develop or build on existing standardization efforts
  • Use of regulatory science for performance standards for  next generation sequencing in vitro diagnostic tests




Botanical Drug Review

  • Foods, dietary supplements, drugs, medical devices, or cosmetics, depending on their “intended use.” ( advertising, labeling, distribution)
  • Unique features: Complex mixtures, lack of a distinct active constituent(s), and substantial prior human use.

 Regulation of Botanical Drugs

 OTC Drug Monograph:  Establishment of standards (monographs or non-monographs) for an OTC therapeutic drug category.

IND, NDA:  For human testing and marketing approval  the product for the proposed use.  CMC Information: Often different from that for synthetic or highly purified drugs.

Botanical Review Team

Guidance for Industry: Botanical Drug Products

Guidance for Industry: Botanical Drug Development..



Juvenile rheumatoid arthritis treatment with model based dosing information



Arthritis causes inflammation of the joints that leads to pain, stiffness and swelling. When arthritis occurs in children younger than age 17, it is called juvenile arthritis.

Some children may experience symptoms for only a few months, while others have symptoms for the rest of their lives. About 300,000 children in the United States have some form of the disease.

Juvenile rheumatoid arthritis (JRA), also called juvenile idiopathic arthritis (JIA). JRA is thought to be an autoimmune disease, the body’s immune system attacks some of its own tissue and cells the same way it would react against a foreign invader such as a virus or bacteria. Certain gene mutations may make a person more susceptible to environmental factors, such as viruses that may trigger the disease.

In JRA, the lining of the joint (called synovial membrane) becomes inflamed and enlarged, limiting movement and causing pain and tenderness. Key symptoms include a rash on the cheeks, sensitivity to sunlight, mouth or nose sores, joint pain, seizures or other signs of neurological problems, and chest pain. Inflamed membranes release enzymes those cause further damage to the bone and cartilage. This type of joint and bone damage may cause problems in a growing kid If the growth areas of the bones are affected, the bones may grow at different rates so that one bone may develop abnormally in shape or size. The result could be, for example, that one leg might be permanently shorter than the other.

There are several subcategories of juvenile rheumatoid arthritis: Systemic onset type (begins with a whole-body), Pauciarticular onset disease (fewer than five joints are affected), Polyarticular disease (five or more joints are affected, usually involves the small joints), Juvenile axial spondylo arthritis (effects involves the large joints of the lower back and hips), Reactive arthritis (exposure from bacteria, in particular shigella or salmonella), Juvenile psoriatic arthritis (have psoriasis, and have a genetic component), and Juvenile systemic lupus erythematosus (cause inflammation and tissue damage in many areas of the body).

MEDICATIONS: (click on underlined for more information)

First lines of medications for an acute stage of the disease are nonsteroidal anti-inflammatory drugs (NSAIDs) to provide relief the inflamed joints. They work by decreasing the amount of an enzyme found in inflamed joints. The same enzyme, however, helps to protect the stomach, so NSAIDs often cause stomach irritation and ulcers. Low doses of NSAIDs are available over-the-counter, including ibuprofen and naproxen. COX-2 inhibitor is a prescription drug that is thought to be safer for the stomach because it does not have as much of an effect on the enzyme that protects the stomach. Children with severe juvenile arthritis have been treated with drugs that suppress the body’s immune response such as corticosteroids and methotrexate. Corticosteroids can have serious side effects, including weight gain, weakened bones, and interference with growth. Other medications may be effective, including hydroxychloroquine, sulfasalazine, leflunomide, azathioprine and cyclosporine. Thalidomide may be effective for certain children with JRA, but care must be taken to avoid pregnancy. Both polyarticular and systemic JIA are treated with biologics.

Biologics target cytokines (control/drive inflammation) such as tumor necrosis factor (TNF), interleukins (IL), and other naturally occurring proteins involved in stimulating the body’s immune response. These are used in the treatment of JIA, generally given intravenously or subcutaneously, includes adalimumab (Humira), etanercept (Enbrel) and tocilizumab (Actemra), Infliximab (Remicade), abatacept (Orencia), anakinra (Kineret), canakinumab (Ilaris) and rituximab (Rituxan). Different biologics tend to work better for different subgroups of the disease.


M&S approach provided appropriate dosing recommendation with the risks and benefits assessments:

  • Exposure-response modeling of canakinumab in the avoidance of flares in children with systemic juvenile idiopathic arthritis Y Xiong  et al., Pediatr Rheumatol. 2013; 11(Suppl 2), 181.
  • Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes. Saik Urien et al, BMC Pharmacology and Toxicology 2013, 14:40

FDA News, Weeks of Oct 26 and Nov 2, 2015


MINUTES : MDUFA IV Reauthorization Meeting : FDA and Industry

  • FDA’s response to Industry’s data request,
  • CDRH information systems for premarket reviews
  • Implementation of the Independent Assessment
  • Financial analysis.


  • Determine schedule for negotiation meetings in 2016
  • FDA to provide add’l information on 510(k) and de novo programs prior to next mtg
  • Next meeting is scheduled on November 18, 2015.


FDA approved


YERVOY (Ipilimumab) injection

Indication: Adjuvant treatment of cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.

Unmet Need: improvement in recurrence-free survival

Reg Pathway: Supplemental BLA, Standard Review


  • Randomized (1:1), double-blind, placebo-controlled trial (n=951), Yervoy vs Placebo
  • Primary Endpoint : Recurrence-free survival (RFS), 26 months vs 17 month, p<0.002


Grade 3-5 immune mediated adverse reactions : Enterocolitis, hepatitis, endocrinopathy, dermatitis, neuropathy
Most common adverse reactions: rash, pruritus, diarrhea, nausea, colitis, vomiting, weight loss, fatigue, pyrexia, headache, decreased appetite, and insomnia.


NUCALA (mepolizumab), injection, for subcutaneous use

Indication: Add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype

Unmet Need:

  • Asthma is a chronic disease causing inflammation in the airways of the lungs
  • Severe attacks can be serious and even life-threatening
  • > 22 million people in U.S. have asthma
  • > 400,000 asthma-related hospitalizations each year

Reg Pathway: Standard, BLA

Mechanism of Action: Humanized IL-5 antagonist monoclonal antibody; IL-5 signaling inhibitor, reduces  production and survival of eosinophils; however, the mechanism of mepolizumab action in asthma has not been definitively established.


  • 1 dose-ranging and exacerbation trial (Trial 1) and 2 confirmatory trials (Trials 2 and 3, n=711), Nucala vs placebo
  • Primary Endpoint : Significantly fewer exacerbations  requiring hospitalization and/or emergency department visits
  • High responder rate with Nucala based on Asthma Control Questionnaire-5 (ACQ-5) and the St. Georges Respiratory Questionnaire (SGRQ)
  • Greater reductions in daily maintenance oral corticosteroid dose, while maintaining asthma control, with Nucala
  • However; no improvement  in lung function with Nucala


  • Most common side effects: Headache, injection site reactions (pain, redness, swelling, itching, or a burning feeling at the injection site), back pain, and weakness (fatigue)
  • Hypersensitivity reactions


GENVOYA (fixed-dose combination tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide)

Indication : Treatment for HIV in  adults and children ages 12 years and older weighing at least 35 kilograms (77 pounds) who have never taken HIV therapy (treatment-naïve) and HIV-infected adults whose HIV-1 virus is currently suppressed

Unmet Need:

  • 1.2 million persons ages 13 years and older are living with HIV infection
  • 50,000 persons unaware of  infection
  • Fixed dose combination of effective, once daily complete regimen


  • 4 clinical trials (n=3,171)
  • Genvoya effective in reducing viral loads and comparable to the other treatment regimens.


  • Boxed Warning  Can cause a buildup of lactic acid in blood and severe liver problems
  • Serious side effects: New or worsening kidney problems, decreased bone mineral density, fat redistribution and changes in the immune system (immune reconstitution syndrome)

Quantitative Systems Pharmacology (QSP)


Use of Quantitative Systems Pharmacology in Pharmaceutical R&D

What :

Quantitative systems pharmacology (QSP) modeling and simulation is integration of two disciplines that have been increasingly useful in pharmaceutical R&D; combination of Systems Biology and Quantitative Pharmacology.

  • Systems Biology is the field of biomedical research including those between genes and biologically active molecules to develop models of these systems that are usually qualitative in nature.
  • Quantitative Pharmacology is the field of biomedical research that seeks to use computer aided modeling and simulation to increase our understanding of the pharmacokinetics  and pharmacodynamics of drugs, and to aid in the design of preclinical and clinical experiments.
  • QSP is a rapidly growing discipline that incorporates computational modeling and experimental methods to investigate drug action.

Traditional pharmacokinetics (PK) has been a major challenge in classical drug discovery: many compounds failed because they had unfavorable PK half-lives or distribution in humans. The traditional PK rarely takes into account the physiology and biology of the human body. However, physiologically based PK (PBPK) is built mainly from drug-independent system information. This has been attributed to a greater connectivity to in vitroin vivo extrapolation (IVIVE) techniques for predicting drug absorption, distribution, metabolism, and excretion (ADME) and their variability in humans. PBPK–IVIVE linked models have repeatedly shown their value in guiding decisions when predicting the effects of intrinsic and extrinsic factors on PK of drugs. Therefore, it will be a better strategy in extending the success of PBPK–IVIVE to pharmacodynamics and drug safety.


QSP combines both computational and experimental methods to validate and apply new pharmacological concepts to the development and use of small molecule and biologic drugs. QPS would maximize therapeutic benefit and minimize toxicity and implement a precision medicine.  QSP models will be critical to increasing the probability of success will be in the target identification stage, the transition from pre-clinical to first in man studies, the transition from healthy volunteer to patient studies, and the transition from adult to pediatric. Modeling and simulation to guide the design of experiments intended to test hypotheses. In addition to the utility in translation between experimental models, QSP allows prediction of the effects of multiple therapeutic interventions in combination. QSP can provide the frame work in which to evaluate the potential combination medications prior to testing in the clinic, by providing a fundamental systems and quantitative understanding of how these different mechanisms will interact. Reported work in the literature described the use of QSP modeling and simulation to facilitate biomedical research and pharmaceutical R&D. Most of these publications have been focused on PK, since the processes that govern drug absorption, distribution, metabolism, and excretion are better established compared to those that govern disease biology and PD. In a report author demonstrated that the use of the physiologically based PK (PBPK) models for prediction of PK in children prior to the conduct of the first pediatric clinical study.. There are software packages available that can be used to develop and run models and it will allow prediction of in vivo drug PK based on the in vitro properties of the molecule.  QSP models that predict both PK and PD are much more complex, and tend to be disease area specific. In an another published work, the QSP model of cognitive deficit in schizophrenia and was able to simulate the enhancement of cognition with clozapine and risperidone, as well as the worsening of cognition with gama-aminobutyric acid modulators lorazepam and flumazenil. Published work can be found in scientific journals like:

CPT: Pharmacometrics & Systems Pharmacology