FDA Brief: Week of October 19, 2015


CDRH prioritization of top 10 needs for regulatory decision making

• Leverage “Big Data”

• Leverage evidence form clinical program as well as other relevant domains

• Improve quality and effectiveness of reprocessing

• Develop computational modeling technologies

• Enhance performance of cybersecurity

• Incorporate human factors engineering principles

• Modernize biocompatibility / biological risk evaluation

• Advance methods to predict clinical performance

• Advance the use of patient reported outcome measures (PROMs)

• Collect and use patient experience/preference


FDA approvedalexionSTRENSIQ (asfotase alfa) administered via injection three or six times per week

Indication : Perinatal, infantile and juvenile-onset hypophosphatasia (HPP). – as the first approved treatment

Unmet Need:

  • Rare, genetic, progressive, metabolic disease leading to severe disability and life-threatening complications
  • Characterized by defective bone mineralization and skeletal abnormalities, muscle weakness, loss of mobility, seizures, pain, respiratory failure and premature death
  • Occurrence estimated one in 100,000 newborns; milder cases in childhood or adulthood more frequent

Reg Pathway : Breakthrough designation, Orphan Drug designation, Priority Review

Mechanism of Action: Replaces enzyme (tissue-nonspecific alkaline phosphatase) responsible for formation of an essential mineral in normal bone


  • 4 prospective, open-label studies (n=99), Alexion vs Natural History Study Group
  • Overall survival (1 yr) : 97% vs 42%
  • Ventilator-free survival (1 yr) : 85% vs 50%
  • Also improvements in growth and bone health, weight, stature, juvenile onset diabetes, healing of rickets


Safety : Injection site reactions, hypersensitivity reactions (difficulty breathing, nausea, dizziness and fever), lipodystrophy, ectopic calcifications of the eyes and kidney.


BELBUCA (buprenorphine) buccal film. Utilizes BioErodible MucoAdhesive (BEMA) drug delivery technology, Schedule III

Indication: Chronic pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

Unmet Need: Novel buccal film delivery system that adds convenience and flexibility.

Mechanism of Action: Mu-opioid receptor partial agonist and a potent analgesic with a long duration of action

Efficacy: 2 double-blind, randomized, placebo-controlled, enriched-enrollment Phase 3 studies in patients with moderate to severe chronic low back pain (n= 1,559). Improvement in pain scores assessed by Numeric Rating Scale (NRS)


  • Risks of addiction, abuse, and misuse which can lead to overdose and death
  • Serious, life-threatening, or fatal respiratory depression
  • Accidental exposure in children can be fatal
  •  Prolonged use in pregnancy can result in neonatal opioid withdrawal syndrome


YONDELIS (trabectedin) injection

Indication:  Treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen

Unmet Need:

  • Liposarcoma and leiomyosarcoma are specific types of Soft Tissue Sarcoma (STS)
  •  STS can form almost anywhere in the body, but is most common in the head, neck, arms, legs, trunk and abdomen
  • In 2014, an estimated 12,000 cases of STS were diagnosed in US

Reg. Pathway: Standard

Mechanism of Action: Alkylating agent; binds guanine residues in DNA, forming adducts, that can affect activity of DNA binding proteins and DNA repair pathways, resulting in perturbation of the cell cycle and eventual cell death.


  • Randomized (2:1), open-label, active-controlled trial  (n= 528), Yondeis vs dacarbazine
  • Investigator-assessed Progression-Free Survival : 4.2 mo. vs 1.5 mo. (P<0.001), Fig 1.
  • Overall Survival: 13.7 mo. vs 13.1 mo. (P= NS)
  • Objective Response Rate : 23 pts vs 10 pts
  • Duration of Response : 6.9 mo. vs 4.2 mo.

Yondelis KM


  • Warning : Severe and fatal blood infections (neutropenic sepsis), muscle tissue breakdown (rhabdomyolysis), liver damage (hepatotoxicity), leakage around the vein or catheter (extravasation), tissue necrosis (breakdown) and heart failure (cardiomyopathy).
  • Other : Nausea, fatigue, vomiting, diarrhea, constipation, decreased appetite, shortness of breath, headache, peripheral edema, neutropenia, thrombocytopenia, anemia, elevated liver enzymes and decreases in albumin


ONIVYDE (irinotecan liposome injection)

Indication: In combination with fluorouracil and leucovorin, for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.

Unmet Need:

  • Pancreatic cancer can be difficult to diagnose early and treatment options are limited especially when the disease has spread to other parts of the body (metastatic disease) and surgery to remove the tumor is not possible
  • 48,960 new cases of pancreatic cancer diagnosed in the U.S. in 2015
  • 40,560 deaths caused by the disease

Reg. Pathway: Priority Review, Orphan Drug Designation

Mechanism of Action: Topoisomerase 1 inhibitor; bind reversibly to the topoisomerase 1-DNA complex and prevent re-ligation of the single-strand breaks, leading to double-strand DNA damage and cell death.


  • three-arm, randomized, open-label trial  (n=417),  Onivyde plus fluorouracil/leucovorin  vs. Onivyde alone vs.  fluorouracil/leucovorin. Onivyde plus fluorouracil/leucovorin performed better than  Onivyde, and vs  fluorouracil/leucovorin. Results of  Onivyde plus fluorouracil/leucovorin   vs  fluorouracil/leucovorin
  • Overall Survival: 6.1 mo vs 4.2 mo (p<0.014)
  • Progression Free Survival: 3.1 mo. vs 5.1 mo.



  • Boxed Warning: Risks of severe neutropenia and diarrhea
  • Other : diarrhea, fatigue, vomiting, nausea, decreased appetite, stomatitis) , pyrexia, lymphopenia, neutropenia), death   due to sepsis

Want to Help the FDA? Become a Consumer Representative on an FDA Advisory Committee

Consumer Representatives serve as Special Government Employees on a committee for up to a four-year term.

Provide the perspective of consumers to advisory committees and do not represent their own personal expertise. Their role is to:

  • Represent the consumer perspective on issues and actions before the advisory committee;
  • Serve as a liaison between the committee and interested consumers, associations, coalitions, and consumer organizations; and,
  • Facilitate dialogue with the advisory committees on scientific issues that affect consumers.


FDA Brief, Weeks of October 5 and 12, 2015

FDA approved


ARISTADA (aripiprazole lauroxil) extended-release injectable suspension, for intramuscular use

Indication: Treatment of schizophrenia

Unmet Need:

  • Schizophrenia is  chronic, severe, disabling brain disorder affecting ~ 1% Americans, mostly < 30 years old
  • Long-acting medications can improve the lives of patients
  •  Availability of  variety of treatment options and dosage forms important to tailor to patient’s needs

Reg Pathway : 505(b)(2). Application relied on investigations not conducted by or for the applicant and no right of reference


  • Leveraged efficacy data from approved oral aripiprazole, ABILIFY, Otsuka Pharmaceuticals
  • Additional data  12-week, randomized, double-blind, placebo-controlled, fixed-dose study (n=622) using Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression Improvement Scale (CGI-I)
  • Demonstration of statistically significantly better PANSS and CGI-I scores versus placebo


  • Boxed Warning (Class labeling): Increased risk of death with off-label
  • Most common side effect  : Akathisia –  urge to move constantly

  • novocure OPTUNE – Device (Class III)


Portable, non-invasive device delivering low-intensity, intermediate frequency, alternating electric fields – referred to as Tumor Treating Fields (TTFields) – that inhibit cancer cell replication and cause cancer cell death.

Unmet Need:

  • 23,000 Americans diagnosed with brain or other nervous system cancers in 2015; >15,000 will die from them
  • 15 percent of all brain tumors -Glioblastoma Multiforme (GBM) – ages 45 to 70; highly resistant tumor, < 15 months survival
  • Need for new treatment option to increase survival

Reg Pathway : Priority Review of PMA supplement

Indication: Expanded indication for newly-diagnosed  GBM in combination with chemotherapy drug temozolomide (TMZ) following standard treatments that include surgery, and radiation therapy and chemotherapy used together.


  • A multinational, open-label, randomized Phase 3 trial (n=695) , Optune  + TMZ vs TMZ alone
  • Superior Progression-free Survival and Overall Survival. – study stopped early based on interim analysis
  • Survival : 19.4 months vs 16.6 months
  •  2-year survival rate  : 48% vs 32% (p=0.0058)

Safety: Skin irritation


FilmArray Meningitis/Encephalitis (ME) Panel


First cerebrospinal fluid (CSF) nucleic acid-based test for simultaneous detection of multiple pathogens that can cause central nervous system infections.   ME Panel uses CSF specimens from patients who have signs and/or symptoms of meningitis or encephalitis.

Unmet need: 

  • Meningitis and encephalitis are inflammatory diseases of the brain and spinal cord; caused by bacterial, viral or yeast infections;
  • Needs rapid treatment – otherwise can cause brain damage and can be fatal
  • ME Panel :
    •  Simple: 2 minutes of hands-on time
      • Easy: No precise measuring or pipetting required
      • Fast: Turnaround time of about 1 hour
      • Comprehensive: 14 bacterial, viral, and fungal targets

Reg Pathway : De novo classification process, a regulatory pathway for some low- to moderate-risk devices that are novel and not substantially equivalent to any legally marketed device.

Indication : Intended as aid in diagnosis of meningitis and encephalitis  when used in conjunction with other clinical and laboratory findings.

Clinical Performance:  Comparison of ME panel results vs other tests (including culture) demonstrated high level of agreement

  • CSF samples (n=1560)  with suspected meningitis/encephalitis
  • CSF Sample (n=150) previously determined to contain microorganisms
  • CSF samples (n=425) artificially prepared with specific concentrations of bacteria or viruses

intelesens Zensor wearable monitor for patients outside the hospital, 510 K Cleareance

  • zensorSmall, battery-powered device that clips on to an adhesive patch which also contains electrodes
  • Collects data on respiration rate, three-lead ECG, heart rate, and motion
  • Data sent via wifi to the cloud, allowing a clinician to access it on a smartphone, desktop computer, or tablet.

nfant NFant Feeding solution , 510 K clearance

nfant feeding

  • Monitor Progress During Feeding TransitionMeasures movement of the tongue on the nipple during pacifier and bottle sucking.
  • 100% PortableSmall NICU footprint. Integrates into normal clinical workflow; minimal setup.
  • User-friendlyFits most standard nipples, pacifiers, and bottles.

BMSOPDIVO (nivolumab) Targeting PD-1/PD-L1 pathway. Supplemental indication

Indication : Treatment for advanced (metastatic) non-small cell lung cancer (NSCLC) whose disease progressed during or after platinum-based chemotherapy.

Unmet Need: 

  • Lung cancer leading cause of cancer death in US; 221,200 new diagnoses and 158,040 deaths in 2015
  • NSCLC most common type of lung cancer, 2 types: Squamous cell and Non-squamous cell (which includes adenocarcinoma)
  • Opdivo blocks PD-1/PD-L1cellular pathway to enable immune system fight the cancer cells

Reg Pathway:

  • BreakThrough designation, Priority Review – Approval 3 months ahead of PDUFA goal!
  • Earlier approval treat advanced squamous NSCLC whose disease progressed during or after platinum-based chemotherapy. This approval expands treatment of non-squamous NSCLC.
  • Additional parallel approval of D-L1 IHC 28-8 pharmDx test (Dako North America Inc. in Carpinteria, CA) to detect PD-L1 protein expression


  • Open-label, randomized study (n=582);  Opdivo vs docetaxel
  • Primary endpoint : Overall Survival – 12.2 months vs 9.4 months
  • Secondary endpoint: Objective Response Rate (complete or partial shrinkage of their tumors). 19% (for 17 months) vs 12% (for 6 months)
  • Level of PD-L1 expression in NSCLC tumors may help identify patients who are more likely to live longer due to treatment with Opdivo. Use pharmDx test to determine potential responders


  • Most common side effects : fatigue, musculoskeletal pain, decreased appetite, cough and constipation
  • Serious  “immune-mediated side effects” on healthy organs, including the lung, colon, liver, kidneys, hormone-producing glands and the brain.

BIPRAXBIND (idarucizumab)

Indication : For use in patients who are taking the anticoagulant Pradaxa (dabigatran) during emergency situations when there is a need to reverse Pradaxa’s blood-thinning effects.  

Unmet need:

  • Pradaxa (anticoagulant) approved for stroke prevention in atrial fibrillation
  • Medical need for reversal of effect in some medical situations to control bleeding

Reg Pathway : Accelerate approval  ( approve drugs for serious conditions that fill an unmet medical need based on an effect on a surrogate or an intermediate clinical endpoint that is reasonably likely to predict a clinical benefit to patients)


  • 3 trials (n=283) healthy volunteers taking Pradaxa. Immediate reduction in the amount of Pradaxa in participants’ blood (measured as unbound dabigatran plasma concentration) that lasted for a period of at least 24 hours.
  • 1 trial (n=123)  patients taking Pradaxa, with uncontrolled bleeding or required emergency surgery. Full reversal of effect in 89% within 4 hrs.

Safety: Headache, low potassium (hypokalemia), confusion, constipation, fever and pneumonia.

FDA Voice

The Merging of Medical Products: Enhancing review of therapeutic and diagnostic combination products

By: Robert M. Califf, M.D. and Jill Hartzler Warner, J.D.

  • Combination products – new , novel approaches
  • Involve new, complex technologies – review  involves the expertise of more than one Center.

FDA Approaches:

◾Issuing more guidance for review of combination products (e.g., our pending draft guidance document on human factors);
◾Enhancing and simplifying data access and sharing for internal staff;
◾Making it easier for staff to request and monitor inter-center consults;
◾Updating and maintaining our internal contact directory for experts to review a combination product; and
◾Improving our internal standard operating procedures for premarket reviews and compliance activities.


FDA Scientific Workshop: Osteoporosis Drug Development – Moving Forward

WHAT : Discuss  clinical development of drugs and therapeutic biologics for osteoporosis treatment. 

WHEN : November 4,  2015, 8:00 am to 5:00 pm

WHERE: FDA White Oak Campus

WHO : Contact[email protected].

REDi new

Regulatory Education for Industry (REdI): Prescription Drug Labeling – Challenges and Issues conference in person or virtually.

WHAT Prescription Drug Labeling – Challenges and Issues

–  Developing the prescribing information 

– Safety considerations to minimize medication errors,

– Patient labeling (e.g., Patient Medication Information), and

– Promotional aspects of labeling.

WHEN : November 3-4,  2015, 8:00 am to 5:00 pm

WHEREBethesda Marriott, Pooks Hill, MD

WHO : Contacthttp://fda.nakamotogroup.com/?source=govdelivery&utm_medium=email&utm_source=govdelivery

Disease Progression Model in Drug Development


Disease progression describes the change of disease status over time as function of disease process and treatment effects. In practice, biomarkers are frequently used as a proxy to monitor disease status. Chronic diseases usually progress slowly over time. For example, Chronic Obstructive Pulmonary Disease  can take well over 10 years to evolve from Stage I (mild) to Stage IV (very severe). It may also take 10 years for Congestive Heart Failure to progress from Stage I (mild) to Stage IV (severe). Late detection and intervention for such chronic diseases significantly increases the burden on both the patients and the healthcare system. Being able to detect the development of chronic diseases at an early stage is instrumental to preventive care and personalized medicine.

A better understanding of disease progression is beneficial for early diagnosis and appropriate individual therapy. There are many different approaches for statistical modelling of disease progression proposed in the literature, including simple path (Linear Progress) models up to complex model. In disease progression modeling (DPM), the progression in time of a disease in an individual is represented as a mathematical function. Initially, a model is produced that characterizes a given disease’s time profile in the absence of therapeutic intervention; this is a base model. Changes due to active treatment are superimposed onto the base model to simulate the effect on the disease of a drug. As the base model is not dependent on any treatment, it may be modified for use in simulating for other treatments. Disease progression models offer greater insight into data obtained from clinical trials, allowing for better study designs. DPM of the progression of a target disease with computational methods is an important technique that can help with the early detection and management of chronic diseases. By characterizing the entire disease progression trajectory, DPM also facilitates disease prognosis improvement, drug development, and clinical trial design.

Linear Progress Model: The linear model assumes constant rate of change of clinical effect or biomarker that reflects the disease status (D) at any time (T) from initial observation from the patient. The rate of change can be defined in terms of baseline disease status (D0) with a slope factor (s), reflects the change from baseline with time:

D(T) = D(0) + s*T

The linear model was further modified by the addition of an effect compartment (Ece) in order to allow for a delay between the initiation of treatment and the time to observable response:

D(T) = D(0) +(Ece(T) + s) *T

In this model, the disease status would not return to the pretreatment course when therapy was discontinued, but would be expected to result in a permanent improvement. Linear equations have been used to describe the progression of several diseases, including Alzheimer’s disease and schizophrenia. In these models, the disease progression component included a placebo response model, incorporating both the trajectory of disease as well as a transient change in disease status attributed to placebo response. DPM is an additional evaluation tool that has an improved ability to detect a drug effect and provides useful dosing information for prescribers. Modeling is also an important component in the regulatory requirements for a new drug application. Models of disease progression have been used for a wide variety of clinical indications. The use of the population approach for studies of disease progression refers to describing the natural history of disease reflected in repeated measures of disease status. Disease status is a general term that refers to any quantifiable variable describing disease at a particular point in time. Observations of disease status, like those of drug concentration or drug effect, can often be made repeatedly in the same patient.

Disease progress models incorporate both pharmacokinetics and pharmacodynamics to describe drug action. Natural history progression models incorporate the clinical and pathophysiological features of disease. By combining them, a more complete picture can be created of the roles of disease and treatments in understanding clinical pharmacology and improving patient care. The use of models to describe the disease progress is good tool that allows the modelers to assess the effect of drug treatment on the time course of disease. The mechanism of action of the drug may suggest innovative combination therapies or novel treatment approaches that would not have been considered without knowledge of the disease and the effect of drug on disease progress. In the literature there are many suggestions of DPM. Each has certain assumptions and models disease progression in a different way.

FDA Brief : Week of September 26, 2015

FDA approved


Novo NordiskTRESIBA (insulin degludec injection) : Long-acting insulin analog

 RYZODEG 70/30 (insulin degludec/insulin aspart injection) : Insulin analog

Unmet Need:

  • 21 million people with diabetes in the US
  • Over time, diabetes increases the risk of heart disease, blindness, nerve and kidney damage
  • Long-acting insulins can improve blood sugar control and can reduce the risk of long-term complications

Indication: Improve glycemic control in adults with diabetes mellitus

 Efficacy : In combination with mealtime insulin

  • TRESIBA : Type 1 diabetes (3 studies, n=1,102) and Type 2 dabetes  (6 studies, n=2,702) patients , over 52 weeks
  • RYZODEG: Type 1 diabetes (1 study, n=362) and Type 2 diabetes (4 studies, n=998), over 26 weeks
  • Reductions in HbA1c (hemoglobin A1c or glycosylated hemoglobin) of  TRESIBA vs  insulin glargine met non-inferiority criteria in both populations

Safety :

  • Should not be in those with diabetic ketoacidosis
  • Hypoglycemia, allergic reactions, injection site reactions, pitting at the injection site (lipodystrophy), itching, rash, edema, and weight gain.



OPDIVO (nivolumab) : Programmed Death receptor (PD-1) blocking antibody

Unmet Need:

  • Melanoma is the fifth most common type of cancer in US
  • 76,100 Americans will be diagnosed with melanoma and 9,710 will die from the disease this year

Regulatory Pathway : Accelerated approval; based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials (Also breakthrough therapy designation, priority review and orphan product designation granted during development)

Indication:  In combination with ipilimumab, treatment of patients with BRAF V600 wild-type, unresectable or metastatic melanoma

Efficacy:  In combination with ipilimumab

  • Single study (n=12)  in patients with unresectable or metastatic melanoma
  • Primary endpoint : Objective Response Rate vs imipilimumab (60% vs 11%) , p<0.001
  • Progression Free Survival (27 vs 23 mo.), p<0.002
  • 14 patients : Duration of ongoing responses is at least 6 months
  • 20 patients : Duration of ongoing responses is at least 9 months


  • Serious side effects : Severe immune-mediated side effects involving healthy organs, including the lung, colon, liver, kidneys and hormone-producing glands.
  • Common side effects : Rash, itching, cough, upper respiratory tract infections, and fluid retention (edema).



KEYTRUDA (pembrolizumab) : Programmed Death receptor (PD-1) blocking antibody

Unmet Need:

  • Lung cancer is the leading cause of cancer death in US
  • Estimated 221,200 new diagnoses and 158,040 deaths in 2015
  • need for targeted therapy

Regulatory Pathway : Accelerated approval; based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials (Also breakthrough therapy designation, priority review and orphan product designation granted during development)

Indication :  Treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy.


  • Subgroup of 61 patients enrolled within a larger multicenter, open-label, multi-part study
  • Patients had tumor proportion score (TPS) of ≥ 50% as  determined by the PD-L1 IHC 22C3 pharmDx Kit.
  • Primary endpoint : Objective Response rate (ORR) 41%; effect lasted between 2.1 and 9.1 months.


  • Severe immune-mediated side effects occurred involving the lungs, colon and hormone-producing glands
  • Uncommon immune-mediated side effects were rash and inflammation of blood vessels (vasculitis)
  • May cause harm to a developing fetus or newborn baby
  • Guillain-Barre Syndrome also occurred.


FDA Voice

Why Partnerships are Key to the Science of Patient Input

FDA’s efforts to incorporate patient perspectives in drug/device assessment and regulatory process


  • Patient Engagement Advisory Committee (PEAC) – posted previously
  •  Will provide advice on complex issues relating to medical devices, the regulation of devices, and their use by patients.


  • Patient-Focused Drug Development (PFDD) – posted previously
  • Obtain patients’ input on specific disease areas, impact on daily life, and available therapies.

Public-Private Partnerships (PPPs)

  • Medical Device Innovation Consortium (MDIC) to advance medical device regulatory science.
  • Kidney Health Initiative (KHI) to understand issues that patients with kidney diseases consider most important
  • Patient Reported Outcomes Measurement Information System (PROMIS) partnership with NIH











Model-Based Drug Development (MBDD)



mbddModel-based drug development (MBDD) is an approach that is used to organize the vast and complex data streams that feed the drug development pipelines of small molecule and biotechnology sponsors. MBDD relies on the construction of quantitative relationships to connect data from discrete experiments conducted along the drug development pathway. These relationships are then used to ask questions relevant at critical development stages, hopefully, with the understanding that the various scenarios explored represent a path to optimal decision making. The FDA critical path document characterizes MBDD as the development and application of pharmaco-statistical models of drug efficacy and safety from preclinical and clinical data to improve both drug development knowledge management and decision-making. Such data streams are ultimately reviewed by the global regulatory community as evidence of a drug’s potential to treat and/or harm patients. As MBDD becomes more integrated into the pharmaceutical research community, a more rational explanation for decisions regarding the development of new agents as well as the proposed treatment regimens that incorporate both new and existing agents can be expected. By providing quantitative justification for trial design, dose selection and decisions during trial execution, MBDD can improve the efficiency of clinical dev elopment. Quantitative clinical pharmacology can also boost the quality of a drug’s regulatory package. The concept of a MBDD paradigm is to construct quantitative expressions about target–drug activity drug-–exposure → exposure–(biomarker) response (efficacy/adverse events) → response–(clinical) outcome relationships, so that these questions promote assumption and scenario testing prior to clinical investigation.

Some examples of the application of MBDD at different stages of drug development include:

Drug Candidate Selection:

Drug discovery and development involve the utilization of in vitro and in vivo experimental models. Different models, ranging from test tube experiments to cell cultures, animals, healthy human subjects, and even small numbers of patients that are involved in clinical trials, are used at different stages of drug discovery and development for determination of efficacy and safety. The proper selection and applications of correct models, as well as appropriate data interpretation, are critically important in decision making and successful advancement of drug candidates.

Simcyp’s (Simulators) R&D activities focus on the development of algorithms along with population and drug databases for modelling and simulation (M&S) of the absorption and disposition of drugs in patients and specific subgroups of patients across different age/sex ranges. Simcyp’s allow predicting the drug absorption, distribution, metabolism and excretion and potential drug-drug interactions. The Simcyp models use experimental data generated routinely during pre-clinical drug discovery and development from in vitro enzyme and cellular systems, as well as any relevant physico-chemical attributes of the drug and dosage forms. A model-based approach can utilize available in vitro and/or in vivo data to predict the pharmacokinetic profile of a drug in humans prior to the first human exposure. These early predictions can be a key component in the rationale for selecting the first dose to administer to humans. Specifically, doses can be selected which are predicted to provide an acceptable safety margin relative to exposures achieved in non-clinical toxicology studies.

Phase 1 Clinical Development:

Early human PK or PD data can be used to develop the next stage of models of human exposure and/or PD response. A real-time model-based approach may be particularly useful to guide dose escalation during the conduct of ascending-dose studies. Upon completion of these studies, simulations based on the final model(s) can be a valuable resource when designing and optimizing longer-term studies.

Phase 2 Proof of Concept:

Data collected at the proof of concept stage can be used to develop ever more robust models. At this stage of development model-based predictions can be critical to selection of study designs, optimal doses, and dosing regimens to progress into Phase 3.

 Phase 3 Clinical Development:

At this stage in development PK and PD (biomarkers) data are typically collected in a broad sample of the target population. These data allow further development of PK and PD models in preparation for regulatory filing and marketing. A key aspect of this stage of MBDD is characterizing the variability in drug concentrations and drug response. Identification of clinically relevant demographic factors (e.g., age, body weight, renal  and hepatic functions) that impact variability is often a critical step in development of these models. Information gleaned from these models often serves as a foundation for developing dosing guidance in special populations (renal/hepatic impairment), age groups (elderly/children) or based on other clinically relevant factors identified in the model.

MBDD is a tool that is increasingly used throughout the drug discovery and development continuum to support fast and rationale decision making and has thereby the potential to accelerate and increase the cost-effectiveness of the drug development process.  The use of suitable biomarkers (PD markers) in MBDD, has shown its merits in therapeutic areas, especially in early clinical development.