Drug Trials DSA and lecture Flashcards
Why are clinical trials conducted?
in order to answer specific questions of safety and efficacy regarding new therapies or devices in humans. These trials include four phases (I-IV) and are most often designed to compare one form of therapy to another experimental form.
Which phases are conduted before the FDA approves the use of a new therapy, usually?
I-III
Federal Pure Food and Drugs Act,
of 1906
prohibited the mislabeling and adulteration of drugs
Food, Drug, and Cosmetic Act
of 1938
required that new drugs be safe as well as pure
Kefauver-Harris Amendment to the Food, Drug, and Cosmetic Act
of 1962
required proof of efficacy as well as safety for new drugs (in response to thalidomide defects)
Drug design approaches
i) Identification or elucidation of a new drug target
ii) Rational drug design based on an understanding of biologic mechanisms, drug receptor structure, and drug structure
iii) Screening for biologic activity of large numbers of natural products, banks of previously discovered chemical entities, or large libraries of peptides, nucleic acids, and other organic molecules
iv) Chemical modification of a known molecule, creation of a “me-too” analog
v) Biotechnology and use of genes to produce peptides, proteins, and information useful as targets, drugs, or diagnostics
vi) Combinations of known drugs to obtain additive or synergistic effects or a repositioning of a known drug for a new therapeutic use
Lead Compound
Chemical compound with pharmacological or biological activity
Structure is used as a starting point for modifications
Improve potency, selectivity, or pharmacokinetic parameters
Result of extensive screening of compound libraries
Recently –> rational drug design
After identification/screening –> preclinical /toxicity testing
Rational drug design
extensive screening of compound libraries against putative disease targets, based on specific targets, such as cell-surface receptors or circulating cytokines, has recently been successful in identifying a lead compound
no-effect dose
maximum dose at which a specified toxic effect is not seen
Minimum lethal dose (LDmin)
the smallest dose that is observed to kill any experimental animal under a defined set of conditions.
Median lethal dose (LD50)
the dose that kills approximately 50% of the animals
Limitations to Preclinical Testing
i) Time and cost – two to six years may be required to collect and analyze animal toxicity profiles and estimate the therapeutic index before testing in humans can begin.
ii) Number of animals used – may be significant to obtain valid preclinical data.
iii) Extrapolation of values – although toxicity and therapeutic values in animals often translate to humans, many do not.
iv) For statistical reasons, rare adverse events that occur in humans are unlikely to be detected in preclinical animal testing.
Caveats in Human Testing
Variable natural history and progression of disease
Presence of other diseases and risk factors
subject and observer bias
crossover design
patients receiving each therapy in sequence so that the patients serve as their own controls
Investigational New Drug (IND)
Current federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines (www.fda.gov)
IND includes: Composition and source of drug Chemical and manufacturing information Animal study data Proposed trial plan Credentials of physician Key preclinical data relevant to study of drug in humans
Institutional Review Board (IRB)
Independent ethics committee (IEC); ethical review board (ERB)
Purpose:
Protect the rights, safety, and welfare of humans participating in research
Authority:
Approve, require modification, or disapprove research
Internal at university/college or independent/commercial
Ethical Conduct of Research in Humans
3 basic principles:
- Respect for persons (autonomous agents with informed consent)
- Beneficence (do no harm, maximize possible benefits)
- Justice- treat individuals and groups fairly and equitably in bearing the burdens of research but also receiving the benefits
Phase 0
(1) A human phase 0 clinical trial (also termed microdosing) is a study whereby small drug doses of prospective drug candidates are administered to human volunteers.
(2) Provide early pharmacokinetic data in humans and may help distinguish whether a candidate drug is promising or inappropriate for further development. Are not meant to provide evidence of efficacy.
(3) In situations when traditional methods such as in vitro and laboratory animal models prove to be unreliable, phase 0 studies can offer supportive and alternative data that allow selection of suitable drug candidates for development.
(4) Financially advantageous since the cost of phase 0 trials is minimal compared to phase I trials.
Phase 1
(1) Typically, the first stage of drug testing in humans.
(2) Conducted to determine the probable limits of the safe clinical dosage range.
(3) Composed of a small number of healthy *** volunteers (20-100).
(a) However, if the drug is expected to produce significant toxicity, as in the case with AIDS and cancer therapy, volunteer patients with disease are included in phase I trials rather than healthy volunteers.
(4) Generally open label with both investigator and subject aware of testing being conducted.
(5) Absorption, half-life, and metabolism are typical pharmacokinetic data reported.
(6) Usually performed in an inpatient clinic at research centers.
Phase III
Purpose:
Further establish drug efficacy and safety
Participants:
Thousands with target disease
Design:
Double-blind, crossover, randomized
Data:
Intent is to evaluate overall benefit-risk relationship
Phase IV
(2) post-marketing study with the purpose to continue to monitor the safety of the new drug under actual conditions of use in large numbers of patients.
(3) For new drugs with side effects that occur with an incidence of 1 in 10,000 patients, the post-marketing feedback provided in phase IV trials are essential.
(4) Rare drug-induced effects or toxicities can be identified with larger populations of patients.
(5) COX-2 inhibitors example – in order to identify that patients taking COX-2 inhibitors showed an increased cardiovascular risks, hundreds of thousands of patients had to be exposed to novel COX-2 inhibitors.
(6) No fixed duration.
New Drug Application (NDA)
(1) A NDA “is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S.”
(2) Every new drug since 1938 has been the subject of an approved NDA application before U.S. commercialization.
(3) Includes full reports of all preclinical and clinical data pertaining to the drug under review.
(4) Duration of approval:
Priority (e.g., cancer chemotherapy) – 6 months
Standard – 13 months
(5) In exceptional situations, the FDA may grant approval of a drug for serious diseases while still in clinical trials and for life-threatening diseases; approval may be granted in a controlled-marketing setting with the requirement that careful monitoring of efficacy and toxicity be carried out.
Control defn
the established therapy (or placebo if non-existent) against which the effficacy of a new agent can be compared
Randomized defn
patients entering the trial have an equal probability of receiving the test or control agent
double blind
neither the health professionals nor the patient know whether the patient is receiving the experimental or control agent
Single blind
the health professionals, but not the patient, know which treatment a patient is receiving
open label
both health professionals and patients know whether the drug is the experimental or control agent
parallel trial
at least two regimens are tested simultaneously, but patients are assigned to only one therapy
crossover trial
patients receive each tehrapy in sequence and therefore serve as their own controls
endpoint
measured to assess a drug’s effect (e.g. blood pressure is the endpoint for testing an antihypertensive agent)
surrogate endpoint
an outcome of therapy that pedicts the real goal of therapy without being that goal (e.g. reduction in tumor size as a surrogate for survival)
Phase II
Purpose:
Determine efficacy
Participants:
100-200 patients with target disease
Design:
Typically, single-blind
Data:
Dosing requirements, toxicities
