Providing your program a path forward….
A clinical pharmacology roadmap, or clinical pharmacology plan, is a great opportunity to prospectively plan your development program for an acceptable PK/PD data package to the FDA for regulatory approval of a New Drug Application (NDA) or Biologics License Application (BLA).
Use Nuventra’s Clinical Pharmacology Roadmap/Plan if your Program is in:
Pre-clinical, Phase 1 and/or Proof of Concept for Phase 2
All drug development programs must address clinical pharmacology, pharmacokinetics (PK), and pharmacodynamics (PD) to enable a successful NDA or BLA. Why not create a plan that’s based on the document the FDA will use to review your program?
While every drug program is different, reviewers in the FDA Office of Clinical Pharmacology use a common guide to assess the suitability of clinical pharmacology and PK/PD information to support label claims for new drugs. The FDA’s Guidance to Industry is called “The Clinical Pharmacology and Biopharmaceutics (CPB) Review Template: The Question-Based Review (QBR)”.
The FDA will use the Question-Based Review (QBR) on your NDA
It is extremely important to utilize this FDA PK/PD guidance document when building your clinical pharmacology, PK, and PD data package. This allows you to evaluate ongoing and planned clinical pharmacology activities for a drug development program and identify any potential gaps.
Nuventra’s Clinical Pharmacology/PK/PD Roadmap evaluates more than 40 different questions that the FDA will ask about your clinical pharmacology, Phase 1, PK/PD data. Nuventra matches this with our extensive experience in clinical pharmacology/PK/PD to prospectively plan a robust clinical pharmacology program.
Don’t wait for the Agency to come to you with these questions, concerns, and gaps in your program. Below are some of the questions from the QBR:
General Clinical Pharmacology Questions
- What are the design features of the clinical pharmacology and clinical studies used to support dosing or claims?
- What is the basis for selecting the response endpoints (i.e., clinical or surrogate endpoints) or biomarkers (collectively called pharmacodynamics (PD)) and how are they measured in clinical pharmacology and clinical studies?
- Are the active moieties in the plasma (or other biological fluid) appropriately identified and measured to assess pharmacokinetic parameters and exposure response relationships?
- What are the characteristics of the exposure-response relationships (dose-response, concentration-response) for EFFICACY?
- What are the characteristics of the exposure-response relationships (dose-response, concentration-response) for SAFETY?
- Does this drug prolong the QT or QTc interval?
- Is the dose and dosing regimen selected by the sponsor consistent with the known relationship between dose-concentration-response, and are there any unresolved dosing or administration issues?
- What are the PK characteristics of the drug and its major metabolite?
- What are the single dose and multiple dose PK parameters?
- How does the PK of the drug and its major active metabolites inhealthy volunteers compare to that in patients?
- What are the characteristics of drug absorption? ( This may include discussion of transporter or pH effect.
- What are the characteristics of drug distribution? (Include protein binding.
- Does the mass balance study suggest renal or hepatic as the major route of elimination?
- What are the characteristics of drug metabolism?
- What are the characteristics of drug excretion?
- Based on PK parameters, what is the degree of linearity or nonlinearity in the dose-concentration relationship?
- How do the PK parameters change with time following chronic dosing?
- What is the inter- and intra-subject variability of PK parameters in volunteers and patients, and what are the major causes of variability?
Intrinsic Factors & Special Populations
- What intrinsic factors (age, gender, race, weight, height, disease, genetic polymorphism, pregnancy, and organ dysfunction) influence exposure (PK usually) and/or response, and what is the impact of any differences in exposure on efficacy or safety responses?
- Elderly Patients
- Pediatric Patients
- What is the status of pediatric studies and/or any pediatric plan for study?
- Race, in particular differences in exposure and/or response in Caucasians, African-Americans, and/or Asians is an important co-variate and should be discussed
- Renal impairment
- Hepatic impairment
- What pharmacogenetics information is there in the application and is it important or not
- What pregnancy and lactation use information is there in the application?
- Other human factors that are important to understanding the drug’s efficacy and safety
Extrinsic Factors & Drug-drug interactions
- What extrinsic factors (drugs, herbal products, diet, smoking, and alcohol use) influence dose-exposure and/or -response and what is the impact of any differences in exposure on response?
- Is there an in vitro basis to suspect in vivo drug-drug interactions?
- Is the drug an inhibitor, inducer or substrate of CYP enzymes? Is metabolism influenced by genetics?
- Is the drug a substrate and/or an inhibitor of P-glycoprotein transport processes?
- Are there other metabolic/transporter pathways that may be important?
- Does the label specify co-administration of another drug (e.g., combination therapy in oncology) and, if so, has the interaction potential between these drugs been evaluated?
- What other co-medications are likely to be administered to the target patient population?
- Are there any in vivo drug-drug interaction studies that indicate the exposure alone and/or exposure-response relationships are different when drugs are co-administered?
- Is there a known mechanistic basis for pharmacodynamic drug-drug interactions, if any?
- Are there any unresolved questions related to metabolism, active metabolites, metabolic drug interactions, or protein binding?
- What issues related to dose, dosing regimens, or administration are unresolved and represent significant omissions?
- Based on the biopharmaceutics classification system (BCS) principles, in what class is this drug and formulation?
- What solubility, permeability, and dissolution data support this classification?
- What is the relative bioavailability of the proposed to-be-marketed formulation to the pivotal clinical trial?
- What are the safety or efficacy issues, if any, for BE studies that fail to meet the 90% CI using equivalence limits of 80-125% ?
- If the formulations do not meet the standard criteria for bioequivalence, what clinical pharmacology and/or clinical safety and efficacy data support the approval of the to-be-marketed product?
- What is the effect of food on the bioavailability (BA) of the drug from the dosage form? What dosing recommendation should be made, if any, regarding administration of the product in relation to meals or meal types?
- When would a fed BE study be appropriate and was one conducted?
- How do the dissolution conditions and specifications ensure in vivo performance and quality of the product?
- If different strength formulations are not bioequivalent based on standard criteria, what clinical safety and efficacy data support the approval of the various strengths of the to-be-marketed product?
- If the NDA is for a modified release formulation of an approved immediate product without supportive safety and efficacy studies, what dosing regimen changes are necessary, if any, in the presence or absence of PK-PD relationship?
- If unapproved products or altered approved products were used as active controls, how is BE to the approved product demonstrated? What is the basis for using either in vitro or in vivo data to evaluate BE?
- What other significant, unresolved issues related to in vitro dissolution or in vivo BA and BE need to be addressed?