Preparing for the Clinic

Abstract

Transitioning from preclinical to clinical development can be both an exhilarating and a sobering experience. At this point, our drug has passed through a rigorous battery of preclinical testing and appears to have the desired efficacy and safety profile and pharmacologic characteristics for advancement to human study. However, embarking upon human experimentation is a serious undertaking. We must ensure that our clinical trial is designed and conducted in as safe a manner as possible. We have an ethical responsibility to ensure that our clinical trial has been designed to optimize the probability of obtaining meaningful results. Furthermore, the drug must be manufactured and quality-tested using exacting standards. This chapter provides an overview of clinical trial design, obtaining clinical grade drug product, and regulatory considerations during the transition into the clinic.

Daria Mochly-Rosen, Ed, Kevin Grimes, Ed.

Key Terms and Abbreviations

Key Terms

• Active Pharmaceutical Ingredient (API): The pharmacologically active molecule.

• Biologics License Application (BLA): Request for permission to introduce a biologic product into interstate commerce in the US.

• Biosimilar: Generic version of a previously approved biologic therapeutic.

• Chemistry, Manufacturing, and Controls (CMC): Manufacturing procedures and specifications that must be followed to ensure product safety and consistency between batches.

• Clinical Endpoint: A measure of something a patient would experience or report.

• Common Technical Document (CTD): Standardized five-module format for submission of regulatory applications to CDER and CBER.

• Contract Development and Manufacturing Organization (CDMO): An external company that does both formulation development and manufacturing of a drug product.

• Contract Manufacturing Organization (CMO): An external company that manufactures a preformulated drug.

• Double-Blinded: Neither the participants nor study staff knows which treatment the participant is assigned to.

• Drug Product (DP): Encompasses API and inactive components such as binders, capsule, etc., that composes the final drug formulation of the pharmacologically active molecule administered to patients.

• Drug Substance (DS): The pharmacologically active biological material—same as API and used interchangeably.

• FDA Center for Biologics Evaluation and Research (CBER): Responsible for regulation of biological and related products such as blood, vaccines, and cellular and gene therapies.

• FDA Center for Devices and Radiological Health (CDRH): Responsible for ensuring the safety and effectiveness of medical devices and the safety of radiation-emitting products.

• FDA Center for Drug Evaluation and Research (CDER): Responsible for regulating the safe and effective use of over-the-counter and prescription drugs, including monoclonal antibodies, immunomodulators, growth factors, and other protein therapeutics.

• First in Human (FIH): A clinical trial in which a treatment is tested in humans for the first time.

• Good Manufacturing Practice (GMP): Exacting procedures and documentation of quality assurance carried out at a certified facility (sometimes referred to as “cGMP” for “current” practice).

• Heavy Chain (HC): The large polypeptide subunit of an antibody.

• Human Equivalent Dose (HED): A dose that is predicted to provide the same level of drug exposure in humans as a dose administered in a preclinical animal model provides in that species (e.g., NOAEL or nontoxic dose); calculated using a species-specific allometric scale based on body surface area.

• Institutional Review Board (IRB): The entity designated to review and monitor research involving human participants in the US; often called the Ethics Committee outside of the US.

• International Conference on Harmonisation (ICH): Organization that provides international guidelines for drug testing.

• Investigational New Drug Application (IND): Request from a clinical sponsor to obtain authorization from FDA to administer an investigational drug or biological product to human subjects.

• Light Chain (LC): The small polypeptide unit of an antibody.

• Master Batch Record (MBR): A written procedure of all manufacturing and testing methods that is required to be approved by QA.

• Master Cell Bank (MCB): Repository of frozen cell aliquots for the clonal hybridoma line selected for biological product manufacturing.

• Master File: FDA file certifying a manufacturing company based on prior IND submissions establishing GMP requirements.

• Maximum Tolerated Dose (MTD): The highest dose of a drug or therapy that does not cause unacceptable side effects or toxicity.

• Media Fill: Manufacturing run using media performed to demonstrate sterile operations.

• Minimal Clinically Important Difference (MCID): The smallest improvement in treatment outcome that a patient would consider worthwhile.

• Multiple-Ascending Dose (MAD): A trial where subjects in each cohort receive multiple administrations of the same dose of study drug, often over 14 days; the dose for each successive cohort is escalated once safety is established for the prior cohort.

• New Drug Application (NDA): Mechanism to obtain FDA approval for the sales and marketing of a new drug in the US.

• New Molecular Entity (NME): A drug product that is a new chemical entity not previously approved by FDA.

• No Observed Adverse Effect Level (NOAEL): The maximum dose administered in preclinical safety studies where no undesirable side effects are seen; sometimes called the nontoxic dose.

• Orphan Indication: An FDA designation of a disease or condition that affects less than 200,000 people in the US or for a treatment that is not expected to recoup its research and development costs due to pricing constraints.

• Pharmacokinetics (PK): Measurements of what the body does to a drug (absorption, distribution, metabolism, and excretion).

• Placebo: A pharmacologically inactive substance used as a comparator in some clinical trials.

• Prescription Drug User Fee Act (PDUFA): US legislation that allows FDA to collect fees from drug manufacturers to fund the new drug approval process.

• Quality Assurance (QA): Process to comprehensively ensure the production of a safe and effective drug product by proactively optimizing the drug manufacturing and packaging process to minimize and eliminate any defects before they can occur.

• Quality Control (QC): Functional unit with the responsibility and authority to ensure that the drug product meets all pre-established quality standards before it is released; this process includes reviewing and approving/rejecting all procedures and components involved in the manufacturing process, from acquisition of raw materials to final packaging.

• Randomization: A method based on chance by which study participants are assigned to a treatment group.

• Recombinant DNA (rDNA): DNA constructs that have been artificially manipulated and do not naturally occur in organisms.

• Single-Ascending Dose (SAD): A trial where subjects in each cohort receive a single administration of a given dose of study drug; the dose for each successive cohort is escalated once safety is established for the prior cohort.

• Sponsor or Applicant: Individual or entity that submits an IND, NDA, or BLA.

• Stability Indicating Assay: Product testing that is performed at designated time intervals to ensure that API remains intact within prespecified levels and that impurities remain below prespecified levels. Often done at both the recommended storage temperature and a higher temperature (e.g., 37 °C), which may accelerate degradation of the drug product.

• Surrogate Endpoint: An indirect measure that may be a lab value, imaging, or clinical measure that is expected to reflect more clinically relevant endpoints.

• Therapeutic BLA: Application submitted to CDER for products such as monoclonal antibodies, cytokines, and growth factors.

• US Food and Drug Administration (FDA): The federal Health and Human Services agency responsible for protecting public health.

• Validation (or Qualification of) Assays: A formal process demonstrating that an assay is specific, reproducible, and precise.

• Working Cell Bank (WCB): Frozen aliquots of cells for active use in manufacturing and testing.

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Key Abbreviations

AAV:

Adeno-Associated Virus

CHO:

Chinese Hamster Ovarian

CFR:

Code of Federal Regulations

CAPA:

Corrective and Preventive Actions

CYP:

Cytochrome P450

DF:

Diafiltration

EMA:

European Medicines Agency

EU:

European Union

EBR:

Executed Batch Records

HPLC:

High-Performance Liquid Chromatography

NIST:

National Institute of Standards and Technology

PMDA:

Pharmaceuticals and Medical Devices Agency

PAI:

Pre-Approval Inspection

PD:

Process Development

QP:

Qualified Person

QSR:

Quality System Regulations

RFP:

Request for Proposal

SOP:

Standard Operating Procedures

SPIRIT:

Standard Protocol Items: Recommendations for Interventional Trials

TSE:

Transmissible Spongiform Encephalopathy

UF:

Ultrafiltration

WRO:

Written Response Only

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