Lecture 3 E1-Drug Dvlpt, Approval Flashcards
What are the centers in the FDA
center for drug evaluation and research
center for biologic evaluation and research
center for devices and radiologic health
center for food safety and applied nutrition
center for veterinary medicine
*all aid in fulfilling FDA requirements of approving a drug
FDA mission
promote and protect public health by helping safe and effective products reach the market in a timely way, and monitoring products for continued safety after they are in use. Our work is blending of law and science aimed at protecting consumers
Step 1 of drug development (shortened)
drug discovery and development
-2-10 years
5000-10,000 compounds
step 2 of drug development (shortened)
pre clinical research and development
-initial synthesis of substances
- lab studies and animal testing
- institutional review boards
-3-6 years
-250 compounds
what is submitted after pre clinical research and development
IND (investigation new drug)
what is step 3 of drug development (shortened)
clinical trial
- research and development ( all trials approved by IRB)
-phase 1- testing in healthy subjects
-phase 2- testing in individuals with the disease
-phase 3- larger scale testing in individuals with disease
-6-7 years
-5 compounds
what is submitted after clinical trials
NDA(new drug application)
what is step 4 of drug development
FDA reviews NDA
-FDA expects review data
-company addresses FDA concerns
-advisory hearing maybe called
-1-2 years
- one FDA approved drug (compound)
what is given after FDA reviews NDA
FDA approval
what is step 5 of drug development
manufacturing
- drug appears on the market
- post market surveillance
- follow up studies and inspections
what is a drug
substance that exerts an action on structure of function of body by chemical action or metabolism and its intended use in diagnosis, cure, mitigation, treatment, or prevention of disease
what is a new drug
one that is NOT generally recognized as safe and effective (GRASE) for the indication proposed
what is found during new drug discovery
identification of an active ingredient or NME (new molecular entity)
- any action or potential to become a drugw
what is the point of drug development process
to provide evidence to prove the drug is effective for indicated uses, that risks associated are known based on reasonable testing, nature of known risks is appropriate with the anticipated benefit for the indication
what are the FDA’s procedures
-current good manufacturing practices (cGMPs)
- good laboratory practices (GLPs)
what is cGMPs
current good manufacturing practices
- quality assurance
-ensuring drugs are consistently produced and controlled to quality standards and appropriate use
what is GLPs
good laboratory practices
-ensuring high quality and reliable test data related to safety of industrial chemical substances and preparations
what is compound centered drug discovery
-producing components that were tested on biological targets (primarily) receptors
- compounds were usually endogenous to the body or found in nature
what is target centered drug discovery
chemical compounds were designed to hit a specific target
- target based therapies
-gene based therapies
what is serendipity
finding one thing while looking for something else
what is lead optimization
the key is to find the right match between target and the chemical compound
how is finding the right match achieved in optimization (4)
- de novo- rational drug design
- high throughput screening (test on different receptors
- combinational chemistry
- serendipity
another name for the right match in optimization
LEAD COMPOUND
- hundreds of manipulations are made to:
maximize receptor affinity
improve pharmacokinetic properties
Preclinical Investigation
- pharmacodynamics+kinetics, and toxicology testing to assess potential therapeutic effects on the NME on living organisms – gather data to determine safety in humans through lab testing in animals
-follow GLPs (correct/safe operations)
– following GLPs requires procedures/ documentation of training, study schedules, processes, status reports submitted to FDA (for approval to clinicals)
-takes 1-3 years
-NO pre approval is required to brgin preclinical evaluation
clinical investigation
- desinged in phases to
1. establish efficacy and safety of rug
2. protect the health and safety of human test subjects
3. ensure the integrity and usefulness of the clinical data study
what are drugs studied in clinical trials called, what are they a part of
drugs studied in clinical trials are called investigational drugs and are apart of the investigational new drug (IND) application
what are some questions the clinical process should answer
-does the drug have effect its supposed to have (PD)
-how much of the drug to give and how often it should be given (PD)
- what side effects are associated with drug and can they be managed (PD)
- how is the drug broken down and how long does it stay in body (PK)
- which foods, drinks, or other drugs can be used at same time or should be avoided
what is the IND application
-sponsor must submit an IND to FDA
(include cover sheet, NME chemistry, protocols, investigation plan, etc)
- after submission wait 30 days before starting trials
- FDA does NOT approve an IND, if FDA doesn’t object within 30 days trials can begin
- may object with concerns or follow up questions of application
ground rules for clinical trials
-clinical study protocol must be developed by sponsor, reviewed and approved by IRB
- all documents (informed consents required) open to FDA inspection at all times
what is the IRB
institutional review board
- oversees research to protect human test subjects and maintains rigorous medical and scientific standards
- review and approved informed consent documents prior to trials (risks, benefits, treatment alternatives)
what is gold standard DBRCT
double blind randomized controlled trial
- patient and person giving dose does not know what is given
what is bias and confounding factors
- want to be sure results are a result of the intervention (not bias/confounding factors)
-confounding factors are additional item that could effect result of study ( when studying lung cancer and smoking- age could be confounding factor)
-bias is encouraging or suggesting one outcome is better than another
what is randomization
-have more than one intervention ( drug and something that isnt the drug but looks like drug)
- participants are assigned to one of intervention groups randomly
( ensure composition is identical, not known which one by patient or MD, drug company)
what is blinding
- reduces being influenced by knowledge
- strategies employed:
make all activities identical
make all treatment items identical (drug)
statistics
- should identify primary outcomes
what is statistical power
calculation of sample size
key is to have sufficient sample size to reach conclusion regarding outcome
want to be sure that if there is a difference between interventions, it can be revealed statistically
what are superiority design comparisons
comparison with a placebo
what are noninferiority design comparisons
confirms that one intervention IS NOT inferior to comparator
what is equivalence design comparison
determines whether one intervention is statistically no different in effectiveness than another
what is continuous efficacy data
interval, ration, mean difference
what is dichotomous efficacy data
all or none items
- only two categories or levels
-ex male or females, yes or no
what is efficacy data expressed as
relative risk reduction (RRR)
absolute risk reduction (ARR)
examples of safety data
adverse event
serious adverse event
the number needed to harm (NNH)
the number needed to treat (NNT)
what is a meta analysis
a quantitative, formal, study design used to systematically assess previous research studies to derive conclusions about the body of research
- guidance to make sure not biased
-analyzing both positive and negative results
IND Phase 1
- established PK profile, safety and dosage
- uses healthy volunteers (no patients with the disease)
- open label
- study size- small- less than 100 subjects
- duration- short- couple of doses, less than year
IND phase 2
-first controlled clinical trial to establish PK profile, safety and efficacy
- phase 2a is pilot study to determine initial efficacy
-phase 2b is controlled study
- single or double blinded
- fast tract conditions allows for people with disease to be a part of study
- study size-medium- several hundred
-duration- weeks to months
IND phase 3
-establish PK profile, safety and efficacy, final formulation, indications, labelling, marketing claims, product stability, packaging, storage conditions
-double blind
-study size-large (hundred to thousand)
- duration- months to years
-final stage before approval!!!!
what is filed to FDA during IND phase 3
notice of compliance to determine whether a drug is approved for widespread use
new drug application (NDA)
goals of new drug application (NDA)
- provide enough information to permit the FDA reviewer to determine whether:
The drug is safe and effective for proposed indications and its benefits outweigh risks
Package insert is appropriate
Manufacturing and quality control methods are appropriate to preserve the drugs, identity, strength, quality, and purity
Three types of action letters after NDA
- Approval letter - all requirements are met, and the company can begin marketing the drug
- Approveable letter – some minor deficiencies, which must be addressed before approval letter.
- Non-approval letter – major concerns with application
what is fast track
Facilitate development, and expedite the review of drugs to treat serious diseases and fill in unmet medical need
Either no therapy exists, or providing better alternative
Priority, review and rolling review
what is accelerated approval
Allowing earlier approval of drugs to treat serious diseases that fill unmet medical need based on surrogate endpoint
- example, survival, or symptom improvement
Post marketing, clinical trials should verify the clinical benefits
What did the prescription drug user fee act create?
Two tiered system of review times -standard review and priority review
what is a priority review
An application will be reviewed within six months (compared to 10 months under standard review)
For drugs that would provide significant improvements in the safety or effectiveness of treatment, diagnosis, or prevention of serious conditions, when compared to standard applications
what is breakthrough therapy designation?
Process design to expedite the development and review of drugs to treat a serious condition with preliminary clinical evidence, suggesting substantial improvement over available therapy on a clinically significant endpoint
When should a breakthrough therapy designation request be received by the FDA
No later than the end of phase 2 meetings
what does phase 4 and post marketing surveillance do
Ensure safety after widespread distribution
This phase is not required, but the FDA may require it for fast track positions
- surveillance, double blind
- study size- very large
- duration- years
what is the FDA’s adverse event reporting system
FAERS
- A database containing received adverse event in medication, error, information, post, marketing
- useful system, looking for new safety concerns, evaluating a manufacturers compliance to reporting regulations and responding to outside request for information
what may happen if a potential safety concern is identified in FAERS
further evaluation is performed
- FDA may take regulatory actions to improve product safety and protect the public health, such as updating a products, labeling information, restricting the use of the drug, communicating new safety, information to the public, or in rare cases, removing a product from the market
how are adverse events submitted?
Reporting adverse events and medication errors by healthcare professionals and consumers is voluntary in the US
They may also be reported to the products manufactures, who are then required to send the report to the FDA, which will then be entered in the FAERS
what is the FDA’s sentinel initiative?
Launched in May 2008, the Sentinel initiative is the national electronic system designed to monitor the safety of FDA, regulated medical products, including drugs, vaccines, Biologics, and medical devices
what does the FDA sentinel initiative do?
Proactively monitors the safety of medical products after they reached the market
Design to complement FDA’s existing adverse event reporting systemv
Uses a distributed data approach, which allows the FDA to monitor the safety of regulated medical products while securing and safeguarding patient privacy
additional drugs/products/procedures
orphan drugs,
generic drugs- abbreviated NDA (ANDA)
OTC regualtions
biologics
devices
regulating drugs and device marketing
What are orphan drugs?
- Drugs are used to treat rare diseases affecting fewer than 200,000 people in the US
- manufacturer has no reasonable expectation of a covering the cost of development
- orphan drug act, 1983 permits, Grant assistance for clinical research, tax credits for R&D, and seven year market exclusivity to the first applicant
what is abbreviated new drug application
ANDA
- used to market generic drugs to provide a safe effective lower cost alternative to the brand name drug
- in the US, a drug patent is valid for 20 years
- all approved brand and generic drug products are listed in the FDA approved drug products with therapeutic equivalence evaluations
What does ANDA not require/ require
ANDA does not require pre-clinical and clinical data, however, must scientifically demonstrate bioequivalence through the rate of absorption, or bioavailability, of the generic drug, which can then be compared to that of the innovator drug
How can a generic drug be approved by the FDA?
To be approved by the FDA the generic version must deliver the same amount of active ingredients in to a patient’s blood stream in the same amount of time as the elevator drug
what is the principle of OTC status?
Wide margin of safety ,method of use ,benefit to risk ration, adequacy of labeling for self medication
what are the four phases of OTC drug review?
advisory panels selection-> expert reccomendations to federal register-> public comments–> fianl criteria by FDA
can be amended by citizen petition and time and extent application (TEA)
Categories of GRASE
generally recognized as safe and effective
category 1- GRASE
category 2- not GRASE
category 3- cannot determine if safe and effective
why couldn’t an OTC product fall under prescription status?
If the FDA deem it to be GRASE
What are Biologics?
- derived from living organisms, such as vaccines, antitoxins, serums blood blood products, therapeutic protein, drugs, derived from natural sources, biotechnology, product, gene or somatic cell therapies, etc.
- require Biologics license application, (BLA)
- CBER deals with BLA
-biologics are treated and tested differently than drugs because of composition
Devices
-any devices with therapeutic claim, ranging from toothbrush to cardiac stent are under FDA jurisdiction
- CDRH is responsible for all regular and radiation emitting devices
- ranked as class 1, 2 or 3, depending on the severity of risk
Violations in enforcement FDA can inspect
FTA has the jurisdiction to inspect manufactures premises and records
-seizure of violative products
enforcements of FDA may include
- warning letter
- recall
1. class 1- if product is seriously harmful
2- class 2- if the product causes temporary or medically reversible
3- class 3- if product is likely to cause adverse side effects
-if company doesn’t comply with results, FDA may seek injunctions against them to the DOJ
limitations to drug approval process
-FDA does not compare competing drugs and rarely requires tests of clinical efficacy for new devices
- FDA does not review advertisements, assess cost effectiveness, or regulate surgery (except for devices)
- postmarketing surveillance of drugs and devices may be inadequate
-pressure for speedy approvals may result in compromise and safety and/or efficacy
- the agency is unnecessarily, slow, and bureaucratic
- conflict of interest (stock ownership, consulting fees, research grants) among some members of that case advisory committees
what is the event rate? (ARR and RRR)
-Proportion of a population experiencing a particular event
-Changes according to baseline risk.
-Depending on disease and risk factors.
What is the RRR?
Relative Risk Reduction
Difference in event rates between two groups expressed as a proportion of the event rate in the untreated group
- percent decrease in risk achieved by group receiving intervention vs group not receiving intervention
20% pts die with treatment A (no treatment) and 15% pts die with treatment B (drug) then the absolute (or actual) risk reduction was 20-15= 5% ARR
5% is arithmetic diff btwn rates, you need to divide 5% by 20% (baseline) to get RRR
.05/.20 x100= 25%
therefore, by implementing drug use you decreased patient risk of death by 25%
What is the ARR
Absolute Risk Reduction
-actual difference in risk between treated and control groups
20% pts die with treatment A (no treatment) and 15% pts die with treatment B (drug) then the absolute (or actual) risk reduction was 20-15= 5% ARR
ARR/RRR example
disease has 40% risk of dying
given that RRR is 25% what is the ARR?
25%= x/40%
x=.100 =10%
ARR is 10%
