Watch this space….
Watch this space….
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.
Learning Objectives: Optimize FDA’s regulation of next-generation sequencing (NGS)-based in vitro diagnostic tests
Botanical Drug Review
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.
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.
MODEL BASED DOSE SELCTION EXAMPLES
M&S approach provided appropriate dosing recommendation with the risks and benefits assessments:
MINUTES : MDUFA IV Reauthorization Meeting : FDA and Industry
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
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
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.
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
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.
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 vitro–in 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