Download Investigational Drugs

Investigational Drugs
Drug Laws, Drug Approval
Process
History of Drug Development
Regulation in the US
• Import Drug Act of 1848: passed after it
was discovered that US troops in Mexican
War were given substandard drugs.
• Purpose: provide for inspection, detention
and destruction or re-export of imported
drug shipments that failed to meet US
standards
History...
• Pure Food and Drug Act of 1906
– Required that drugs not be mislabeled or
adulterated and they must meet recognized
standards for strength and purity
– Mislabeling: identity or composition of drugs
• Sherley Amendment 1912:
– Prohibited false therapeutic claims for drugs
History….
• Food, Drug and Cosmetic Act 1938
– After 107 people died after taking
sulfanilamide prepared in diethylene glycol
(solvent similar to ethylene glycol (antifreeze)
– Purpose: require safety of drugs when used in
accordance with the labeled instructions; be
proven through testing before marketing
• Submission of NDA to the FDA first established
History….
• Durham-Humphrey Amendment 1951
• Purpose: divide drugs into 2 categories:
– OTC (safely self-administered)
– Rx (potentially dangerous side effectsrequired medical expert supervision)
• Required following statement on all Rx
labels: “Caution: Federal Law prohibits
dispensing without a prescription”
History...
• Kefauver-Harris Drug Amendment 1962
• Purpose: 1)Manufacturer has to
demonstrate proof of _________and
_______ prior to marketing any new drug.
2) manufacturer comply with CGMP
(current good manufacturing practices. 3)
FDA has to formally approve an NDA
before drug is marketed.
History...
• 1992 PDUFA (Prescription Drug User Fee
Act): Defines time frames for NDA reviews
and establishes revenues to fund
increased demands on new time frames
for approval process.
• 1997 FDAMA (Food and Drug
Administration Modernization Act): Allows
other technology to facilitate regulatory
review process (FAX, Internet etc)
History…...
• ICH (International Conference on
Harmonization): Cooperation between
Japan, Europe, US to develop common
guidelines for ensuring quality, safety, and
efficacy of drugs between countries.
• Goal: ensure a method for submission and
rapid regulatory approval in approval
process and availability world wide
Drug Approval Process
Step 1
• Pre-Clinical Drug testing
– In vitro or animal testing
– Develop a pharmacologic profile of the drug
– Determine acute toxicity in at least two
species of animals
– Conduct short term toxicity studies (2 weeks3 months)
Investigational New Drug
Application (IND)
• File IND with the FDA
– Contains chemical information, preclinical
data, detailed description of planned clinical
trials.
• Purpose: to get approval to begin clinical
trials in humans.
– It can only be filed after the study sponsor
has identified the pharmacological profile of
the drug and has results from both acute and
short term toxicity studies in animals.
FDA Responsibilities for the
IND
• IND will be forwarded to one of nine
divisions for review based on
therapeutic category of the drug
• FDA has ____ days after the receipt of
the IND to respond to the sponsor.
• After this 30 days the sponsor can begin
clinical trials if no response from FDA
w/in 30 days. FDA will respond with a
“clinical hold” w/in 30 days to stop
clinical trial initiation.
Clinical Trial Phases
Phase 1
• Purpose: determine basic safety and pharmacologic
information.
– To identify preferred route
– To identify safe dosage range
– To identify toxicity
– Pharmacokinetics
• Treat: 20-80 patients over 6 months-1 year
– healthy adult volunteers w/ no pre-existing
conditions, or in patients who have exhausted all
other options (cancer patients, AID’s patients)
– use cautious (low) dosages
Phases of Clinical Trials
Phase II
• Purpose: Evaluate the study drug in
subjects who suffer from the disease or
condition that the drug is proposed to
treat.
– Evaluate efficacy
– Identify group of patients most likely to benefit
• Treat: 100-200 patients over 2 year
duration
Phases of Clinical Trials
Phase III
• Purpose: Further define efficacy and
safety
• New agent compared to current therapy
• Trials usually multicenter studies
– Treat 600-1000 patients
– Last 3+ years
– These trials serve as basis for ______ for
marketing approval
New Drug Application (NDA)
• After phase 3 trials completed, sponsor
submits NDA to the FDA requesting
approval for marketing.
• Includes: pre-clinical data, clinical
data,2 well designed controlled clinical
trials info, manufacturing
methods,kinetics, pharmacology,
product quality assurance, relevant
foreign clinical testing, published
reports, proposed package insert for
Phase IV (Post Surveillance
Studies)
• Drug is on the market.
• Purpose: gather more data on safety and
efficacy and identify an advantage over other
therapies
• These are conducted for the approved
indication, but may evaluate:
– different doses
– effects of extended therapy
– drug’s safety in other populations
(pregnancy, children, elderly)
Drug to Market Approval
Process
• Initial synthesis of an agent to approval
of NDA = 8-9 years.
• NDA process = ave. 2 years (2 mo.-7
yrs)
• Procedures to expedite process for
AID’s, Cancer drugs etc.:
– Emergency Use IND
– Parallel track
– Treatment IND
– Compassionate IND
Emergency Use IND
• Purpose: allow shipment of drug by
sponsor for desperately ill patients prior to
the submission of an IND.
– Can only be used for life threatening diseases
where all other options have been exhausted.
– FDA approval required and must authorize
– IRB approval not required
Parallel Track
• Purpose: increase accessibility of
experimental drugs for AIDS patients.
– Drug becomes available after phase I studies
to patients who are ineligible for enrollment
via controlled trials and are unable to benefit
from current therapies.
– Drug is still monitored for safety and efficacy
while clinical trials going.
Treatment IND
• Purpose: accessibility of experimental
drugs for desperately ill patients.
– Criteria for use:
• drug must be intended to treat a serious or
immediately life threatening disease.
• No other alternative therapies
• Drug is under investigation in CCT (clinical trials)
• Sponsor must be actively pursuing FDA approval
Treatment IND
• 2 categories of treatment IND:
– life threatening conditions (death likely in
months)
• Tx allowed with drug after phase II but earlier than
phase III.
– serious conditions (disease causes
irreversible morbidity- Alzheimer’s)
• tougher requirements for safety and efficacy
• tx allowed with drug during phase III or later.
Compassionate Use IND
• Individual investigator IND
– allow release of drug for use on a single
patient basis.
– Use this IND to obtain a drug from a foreign
country for emergency use in a single patient.
– Both FDA and IRB approval are required.
Expedited Approval Process
• Accelerated Drug Approval Program
– Used when drug is intended for tx of serious
or life threatening condition and no other drug
works in same way for condition.
– Can be approved as early as post-phase II.
– Needs 2 pivotal phase II studies completed.
– FDA can put restrictions on marketing and
distribution
Orphan Drug Act (1983)
• Provides incentives for manufacturers to
develop orphan drugs
• Orphan drug: Drug used for tx of a rare
disease (affecting fewer than 200,000
people in US) or one that will not generate
enough revenue to justify the costs of
research and development.
Orphan Drug Act Incentives
• Tax incentives: sponsor is eligible to receive
50% tax credit for money spent on R&D
• Protocol assistance: if drug shown to be used
for rare disease, FDA will provide assistance
in pre-clinical and clinical trials
• Grants and contracts: FDA budget may allot
up to $12 million/yr for developing orphan
drugs
• Marketing exclusivity: 1st sponsor of orphan
drug is allowed 7 years of marketing
exclusivity for that indication.
Generic Drug Approval Process
• Manufacturer submits an Abbreviated New
Drug Application (ANDA) to obtain FDA
approval to market the drug.
• ANDA data is submitted to the Center for
Drug Evaluation and Research (CDER).
• CDER provides the review and approval of
a generic drug product.
CDER (Center for Drug
Evaluation and Research)
• Approves generic drugs manufactured in the US
– checks patent laws before approval
• Approves imported drug products
– prevents unapproved new drugs or misbranded
drugs from entering our country.
– Issue product certifications to foreign
governments-- state that these products are
manufactured according to the GMP (good
manufacturing practice) bylaws.
Generic Drug Manufacturer
Requirements
• Document its compliance with GMP
• Provides full description of facilities used for
manufacturing, packaging, labeling, and quality
control
• Demonstrates bioequivalence to the brand drug
• Provide a chemistry review to assure it is manuf. in a
reproducible manner under controlled conditions
Role of the Pharmacist in
Investigational Drug Process
• Serving on the Institutional Review Board
(IRB)- sets up guidelines, reviews financial
evaluations, review of proposal to investigate
• Disseminating communication (preparation of
DDS (drug data sheets), protocols for IDP
• Accountability records of drug usage
• Ordering, maintaining, returning drug supplies
for clinical trials
• Randomizing and blinding drugs for trials
• Reporting adverse events
• Preparing the IND
Investigational Drug Procedure
(IDP)
• When reviewing protocol for clinical trial, it
should contain:
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Name and synonyms of study drug
Chemical structure of study drug
Mechanism of action of study drug
Dosage range, route of administration
Animal toxicologic and pharmacologic info
Dosage form and strength to be supplied
Preparation guidelines (stability, compatibility)
Storage requirements, toxicities
Drug Data Sheet (for use by
Pharmacy, Nursing, MD’s)
• Drug name and synonyms, status, chairperson of
study
• Therapeutic class, mechanism of action
• Pharmaceutical data
• Stability and storage data
• Dose preparation guidelines
• Usual dosage range, route of administration
• Side effects, toxicities
• Effective dates
• References