| - ASSESS THE SAFETY OF A DRUG OR DEVICE
- take several months to complete
- includes a small number of HEALTHY VOLUNTEERS paid for participating in the study
(20 TO 100)
- DETERMINE THE EFFECTS OF THE DRUG OR DEVICE ON HUMANS including how it is absorbed, metabolized, and excreted (ADME)
- investigates the side effects that occur as dosage levels are increased.
- 70% OF EXPERIMENTAL DRUGS PASS THIS PHASE OF TESTING
- represent the FIRST USE OF THE DRUG IN MAN
- Except for certain special situations such as for many cancer and AIDS drugs where no truly safe dose can be anticipated, these studies are performed in normal healthy volunteers.
- purpose is to establish a dose-response tolerance relationship, limited by the onset of unacceptable adverse effects. | Phase 1 Investigation |
| Phase 1 Investigation
TWO MODES OF DOSING | 1st- is an INCREASING SINGLE DOSE either daily or every alternate day
2nd- involves MULTIPLE DOSING at each level prior to INCREASE. No determination of efficacy is usually possible at this stage generally not blinded and take about 1 year to complete
Once this tolerance and safety screen is complete, the studies advance into efficacy and tolerance in patients. |
| Goals of Phase 1 Testing
1 PREPARATION OF PROTOCOL
2 INITIAL GOALS | .
1 Normal Subjects
2 MEASURE THE PHARMACOLOGICAL IMPACT, to determine the pharmacokinetic behavior and to detect untoward effects.
- Sponsor must go back to the animal data to REVIEW EXACTLY WHICH ORGAN SYSTEMS HAVE SHOWN A RESPONSE TO THE DRUG so as to pick out which human systems need to be monitored. |
| Considerations in Design of Protocol
1 drug is designed to treat a disease state such as cancer or infection and its impact can only be measured in terms of __
2 the primary goal of such Phase I studies are in the __ | .
1 AMELIORATION OF THE DISEASE
2 PHARMACOKINETIC AREA and in the DOCUMENTATION OF ADVERSE EFFECTS. |
| Essential Pharmacokinetic Data in Drug Testing:
1 identification of metabolites, plasma protein binding, clearance, volume of distribution, plasma half-life, peak plasma concentration, time to peak, area under the curve
2 Considerations of the Principal Investigator: Once protocol has been established by the sponsor, the next step is to find __ to carry out the study. | .
1 Oral availability, urinary excretion
2 INVESTIGATOR |
| ESSENTIALS in Planning a Phase I Trial: | 1. subject population – normal subjects
2. facilities
a. area for study; hospitalization
b. collaboration
c. laboratory facilities
3. Time commitments
4. Ancillary personnel
5. Budget
6. Administrative approval
7. Institutional Review Board (IRB) approval
SFT ABAi |
| A CRITICAL ADMINISTRATIVE ELEMENT in all institutions in which HUMAN RESEARCH IS BEING DONE.
Has the AUTHORITY TO EXAMINE AND ANALYZE the PROTOCOL OF ANY RESEARCH PROPOSAL involving human subjects to ensure that such research correctly balances the potential benefits against risks to which the subject will be exposed and to specify what information must be presented to the subject before he or she can be said to have given informed consent. | The Institutional Review Board (IRB) |
| The Institutional Review Board (IRB)
Questions | 1. Is everything clearly in understandable lay language?
2. Is the preclinical data base sufficiently comprehensive?
3. Are subjects appropriately screened?
4. Are risks accurately and fully described?
5. Are benefits realistically estimated?
6. Does the pregnancy clause receive sufficient emphasis?
7. Are subjects assured of privacy and confidentiality?
8. Are the recompense and liability conditions clearly and expressly stated?
9. Is the subject’s freedom to withdraw or refuse expressly preserved?
10. Are the rights of minors or incompetents protected by signatures of parents or guardians?
11. Does each subject receive a copy of the consent form with the name and telephone number of someone on the investigational team?
12. How much is research vs. routine clinical?
13. Someone to call re research subjects rights. |
| Management of Phase I Clinical Trial | 1 Disappearing time
2 Disappearing subjects
3 Disappearing drug
4 Disappearing data |
| subjects and time must be lined up in advance so that no unforeseen delays will upset the schedule unduly, planning is the answer. | Disappearing time |
| a change of mind, unexpected emergencies, illness etc, hence it is always desirable to recruit a greater number than required | Disappearing subjects |
| 1 every ampule, every milliliter, every tablet should be accounted for. In a perfect trial, there is no disappearance of the drug.
2 every bit of data is in place | 1 Disappearing drug
2 Disappearing data |
| - Studies test the EFFICACY OF A DRUG OR DEVICE.
LAST FROM SEVERAL MONTHS to TWO YEARS, and involves up to several hundred patients
(100-300 PATIENT VOLUNTEERS)
- RANDOMIZED TRIALS - 1 group of px receives the EXPERIMENTAL DRUG, while a 2nd "control" group receives standard treatment or PLACEBO.
- studies are "BLINDED", neither the patients nor researchers know who has received the experimental drug.
- allows investigators to provide the pharmaceutical company and the FDA with comparative information about the relative safety and effectiveness of the new drug.
- intended to determine, BY ASCENDING DOSES, the multiple dose drug level required for a therapeutic response; clear recognition of the lower levels for adequate therapeutic response> > minimize ADR
- EFFECTIVE DOSE be found by rapidly increasing the dosage within the parameters determined by the Phase I study.
- evaluate STEADY-STATE MAINTENANCE LEVELS. | Phase II Investigation |
| 1 be found by rapidly increasing the dosage within the parameters determined by the Phase I study.
2 patients in Phase II studies will NOT be exposed to the highest drug level reached for __
3 However, it is possible for Phase II patients to carry over into __ for longer terms
4) __% of drugs entering Phase II will proceed to the next phase. | 1 effective dose
2 more than 2 weeks
3 Phase III studies
4) 40% |
| In phase 2, it is used to evaluate __ levels | steady-state maintenance levels. |
| At the end of phase 2, FDA and sponsor discuss __ | how large - scale studies in phase 3 will be done. |
| - RANDOMIZED & BLIND TESTING
- hundred to several thousand patients (1,000 to 3,000) and MORE DIVERSE (in age, sex, health etc) to confirm efficacy and safety.
- provides the pharmaceutical company and the FDA with a MORE THOROUGH UNDERSTANDING OF THE EFFECTIVENESS of the drug or device
- benefits and the range of possible ADR.
- Complete>> a pharmaceutical company CAN REQUEST FDA APPROVAL for MARKETING THE DRUG.
- In general, unless indicated by the Phase II studies, it is UNLIKELY THAT PATIENTS in Phase III studies will be UTILIZED FOR ROUTINE BIOPHARMACEUTIC, PHARMACOKINETIC EVALUATIONS
- Phase III processes, PATIENTS WITH MORE THAN ONE DISEASE CONDITION WILL ENTER THE STUDY
- The potential of other medications to effect or be affected by the test drug should then be examined carefully. | Phase III Investigation |
| PREDICT EFFICACY MORE QUICKLY than by these conventional clinical criteria
a QUANTITATIVE MEASURE that ALLOWS US TO DIAGNOSE AND ASSESS THE DISEASE PROCESS and monitor response to treatment.
FDA >> surrogate endpoint = a laboratory measurement or a physical sign used as a substitute for a clinical endpoint.
Ex: Low bone material density> > Improve bone material density | Biomarkers and Surrogate Endpoints |
| a LABORATORY MEASUREMENT OR A PHYSICAL SIGN used as a SUBSTITUTE for a CLINICAL ENDPOINT.
Ex: Low bone material density> > Improve bone material density | FDA >> surrogate endpoint |
| FDA allow patients w/ life threatening disease to begin using new therapies before formal FDA approval
Under this, patients may receive investigational drugs that have shown promise in Phase II clinical trials.
Patients are INFORMED THAT THEY ACCEPT SOME RISK in using drug products NOT YET APPROVED but seriously ill patients are typically willing to accept more risk. | Early Access |
| STEPS IN NEW DRUG | STEP 1 From the Drug Company
- Scientists discover a new compound with the potential to become a meaningful medicine
- Drug companies test drugs on animals to learn more about its safety and how it works.
STEP 2 IND submission
- Drug company submits an investigational New Drug (IND) application to the FDA.
STEP 3 IND review:
FDA works to ensure proposed Clinical trials:
- Do not place participants at extreme risk or harm
- Provide informed consent and
STEP 4 NDA SUBMISSION:
- Company submits a new drug application, including the results of all trials, as well as manufacturing information, to the FDA
STEP 5 NDA ACCEPTANCE and review: 60 days later, FDA decides if it will accept the NDA
After 10 months, review the application for drugs that offer only minor improvements.
After 6 months for drugs that offer major advances in treatment. |
| 1 Before approval, the FDA:
2 Final step is the __ by which the FDA reviewers will approved the application or issue a response letter | 1) 1 REVIEWS AND APPROVES THE LABEL FOR THE DRUG to make sure it includes important information healthcare professionals and patients need to know
2 INSPECTS THE FACILITY where the drug will be manufactured.
2 DRUG APPROVAL |
