PCOL 310

food

(1) articles used for food or drink for man or other animals, (2) chewing gum, (3) articles used for components of any such article ◦The components that went into making the food is food

primary pharmacodynamics studies

In vivo and/or in vitro studies, assessing mode of action/effects of candidate compound on the target

fast track designation

- a drug intended to treat a serious condition and clinical or nonclinical data demonstrate it has the potential to address an unmet medical need - a qualified infectious disease product

breakthrough therapy designations

- a drug intended to treat a serious condition and preliminary clinical evidence shows the drug may demonstrate substantial improvement or a clinically significant endpoint over available therapies

accelerated approval pathway

- a drug that treats a serious conditions and generally provides a meaningful advantage over available therapies the drug demonstrates an effect on: - a surrogate endpoint that is reasonable likely to predict a clinical benefit or -a clinical endpoint that can be measured before irreversible morbidity or mortality (IMM) or -the drug is reasonably likely to predict an effect on IMM or on an intermediate clinical endpoint

priority review designation

- an application (original or efficacy supplement) for a drug that treats a serious condition and if approved would provide a significant improvement in safety or effectiveness -any supplement that proposes a labeling change related to pediatric studies - an application for a drug that has been designated as a qualified infectious disease product -any application or supplement for a drug submitted with a priority review voucher

seizure

-An action brought against an FDA-regulated product because it is adulterated and/or misbranded within the meaning of the Act. The purpose of such an action is to remove specific violative goods from commerce.

prescription drug label

-Commercial container label- (remember this is for the health care professional not the consumer The principal display panel (PDP) is the panel of a label that is most likely to be displayed, presented, shown, or examined by the end user.

when is a product a drug

-Did supplier make a health or therapeutic claim or a structure/function claim? -Was the article intended to diagnose, cure, mitigate, treat or prevent a disease or was it intended to affect the body structure or function? -Manufacturer's intent is controlling, not the purchaser's. -Mere use by purchasers, where the supplier doesn't intend the product to be used therapeutically doesn't make the article a drug. -Look at the claims of the product in advertising/marketing -What if a dietary supplement has a compound that was approved as a drug?

NDC code

-Drug Listing Act of 1972 requires manufacturers provide the FDA with a current list of all drugs manufactured, prepared, propagated, compounded, or processed by it for commercial distribution. -Drug products are identified and reported using unique three segment number used to identify the manufacturer, the drug, and the package size. -NDC number: 1234-5678-90 -1234=Manufacturer -5678=drug -90=package

inspections/enforcement

-FDA inspectors DO NOT need a warrant to perform an inspection during business hours -Enforcement by FDA -Injunction- cause a violator to stop its illegal activity -Criminal proceedings- jail time and/or fines -Seize adulterated or misbranded food, drugs, cosmetics -Send warning letters -Corporate officer liability- officers can be convicted when their employees violate FDCA- without proof they acted intentionally or with negligence and even if they had no knowledge of the offense. -Product Recalls- FDA has authority or manufacturer can voluntarily recall; manufacturer responsible for contacting consumers. PHARMACIST responsible for knowing which drug products have been recalled. Pharm publications often list; available on FDA site:

label vs labeling

-Label: Display of written material on the product's container and on the outside container or wrapper, if any. -Labeling: All labels and other written, printed, or graphic matter on any container or wrapper or material accompanying the product Includes: -Package insert -Drug advertisement -Information in publications (PDR) -Promotional materials, including newsletters, and literature

what authorities were given to FDA by Kefauver-Harris amendment of 1962

-Manufacturers must prove the effectiveness of drug products before they go on the market, and afterwards report any serious side effects. -Evidence based on adequate and well-controlled clinical studies conducted by qualified experts. -Study subjects would be required to give their informed consent. -Gave FDA 180 days to approve a new drug application -FDA conduct a retrospective evaluation of the effectiveness of drugs already approved for safety between 1938 and 1962. -Allowed FDA to set good manufacturing practices for industry and mandated regular inspections of production facilities. -Transferred to FDA control of prescription drug advertising, which would have to include accurate information about side effects. -Controlled the marketing of generic drugs to keep them from being sold as expensive medications under new trade names.

nonprescription drug labeling requirements

-Nonprescription drug labeling requirements 21 CFR § 201.60 et seq. -General provisions: -Drug must bear the name and place of business of the manufacturer, packer, or distributor. -Manufacturer is the person who performs all of the following operations that are required to produce the product: (1) Mixing, (2) granulating, (3) milling, (4) molding, (5) lyophilizing, (6) tableting, (7) encapsulating, (8) coating, (9) sterilizing, and (10) filling sterile, aerosol, or gaseous drugs into dispensing containers. -Display panel-DRUG FACTS -All nonprescription, over-the-counter (OTC) medicine labels have detailed usage and warning information so consumers can properly choose and use the products.

research (non-commercial)

-Physician-submitted IND applications are generally considered research INDs when they are not trying to bring a new drug to market. Instead, their clinical research may be intended to prove efficacy for a new indication or dosage of an already approved drug. THINK CLINICAL RESEARCH DONE TO TEST A THEORY OR IMPROVE USE OF EXISTING TREATMENTS

data monitoring committees (DMC) responsibilities

-Safeguard the interests of study patients -Preserve the integrity and credibility of the trial in order so that future patient may be treated optimally -Ensure that definitive and reliable results be available in a timely way to the medical community

drug price competition and patent term restoration act 1984 - Waxman Hatch amendment

-Streamlined GENERIC drug approval process to make them more readily available -Created: -Market and patent exclusivity periods for both branded and generic drug companies. -Patent term extension to adjust for delays caused by the FDA approval process. -A unique patent litigation process triggered by a generic drug company's submission of an application for FDA approval.

what does the FDA recommend that the PDP include on the critical information for the commercial container label

-The principal display panel (PDP) is the panel of a label that is most likely to be displayed, presented, shown, or examined by the end user. FDA recommends that the PDP include the following critical information: -Name, logo, and place of business of manufacturer, packer or distributor -NDC number -Proprietary name, established name or proper name -Generic name -Ingredient information, including quantity and proportion of each active ingredient; names of inactive ingredients -Quantity in terms of weight or measure (e.g., 100mg) -Net quantity of the container (e.g.,100 tablets) -Recommended or usual dosage or reference to package insert -Route(s) of administration -Warnings (if any) or cautionary statements (if any) -Rx-only statement (legend) -expiration date- if listed in only month and year, it means the last day of the indicated month. -Statement specifying type of container to be used in dispensing -Bar code/control number/lot number If the container is too small, the recommended dosage, route of administration, inactive ingredients, and statement regarding type of container can be included in other labeling on or within the package.

commercial

-When a drug company or sponsor, like the National Cancer Institute, submits an IND application, it is generally considered a commercial IND. The intended purpose of their clinical research is to collect the data needed to bring the drug to market.

module 4 - nonclinical study reports

-adequate information about the drug's pharmacology and toxicology (in vitro or animals studies) to support use in humans -pharmacological effects and drug disposition study reports -pharmacodynamics (primary/drug interactions) -pharmacokinetics (ADME/analytical methods/validation) -toxicology (summary of toxicological effects in animals and in vitro; results of acute/subacute/chronic toxicity tests); carcinogenicity; reproduction/developmental toxicity/fetal effects; special toxicity tests due to mode of administration) literature references

expanded use

-also called "compassionate use" -pathway for a patient with an immediately life threatening condition or serious disease to gain access to an investigational drug (or product or biologic) treatment outside of clinical trials

module 5 - clinical

-human clinical study reports and related information -protocols -FDA form 1572 -investigator CVs -previous human experience (clinical study reports) -other clinical reports [human PK and PD studies, efficacy and safety studies, antibacterial microbiology/special pathogens, literature references] *clinical summary (module 2)

DMC member tasks

-initial review evaluate quality of -ongoing study conduct -assess safety and efficacy data -review final results

criminal prosecution

-may be recommended in appropriate cases for violation of Section 301 of the Act.; -Misdemeanor convictions, which do not require proof of intent to violate the Act, can result in fines and/or imprisonment up to one year. -Felony convictions, which apply in the case of a second violation or intent to defraud or mislead, can result in fines and/or imprisonment up to three years.

GMP

-set of regulations that establishes minimum requirements for the methods, facilities, or controls used in the manufacture, processing, packaging, or holding of a drug product. -Applies to manufacturers, not pharmacies, unless the pharmacy engages in activities where they could be deemed manufacturers -Manufacturers must be registered with the FDA and are normally inspected EVERY 2 YEARS -Confirm that the production and control procedures result in the proper identity, strength, quality and purity of the drugs -Identify deficiencies -Ensure correction of deficiencies -Drugs subject to GMP are selected based on medical importance, market share, number of similar products in the marketplace, and previous compliance record of manufacturer

components of a study protocol for RCT

-study rationale -study objectives (primary, secondary) -study design -criteria for evaluation -participant selection -screening (of participants) -study intervention(s) -study procedures and guidelines -adverse event reporting and documentation -discontinuation and replacement of participants -protocol violations -data safety monitoring -statistical methods and considerations -data collection, retention, and monitoring -administrative, ethical, and regulatory considerations

seizure

-the physical isolation of a drug while FDA or state agency files civil lawsuit - FDA can seize drugs that are "misbranded" or "adulterated"

IND purpose

1)Notifies regulators of intent to begin clinical studies in the US 2)Provides preclinical data indicating that the drug is reasonably safe to administer to humans 3)Provides information about manufacturing process and chemistry background 4)Describes the initial clinical study being proposed 5)Provides assurance that an Institutional Review Board (IRB) will approve the study before it begins

what are the 5 elements of informed consent and assent

1. a statement that the project is research and participation is voluntary 2. a summary of the research, including: purpose, duration, list of procedures 3. reasonable, foreseeable risks or discomforts 4. reasonable, expected benefits 5. alternative procedures or course of treatment, if any

history of drug regulation

1906 pure food and drug act - started to want to make sure what was in the bottle said it on the bottle

investigational new drug (IND)

A "new drug or biological drug that is used in a clinical investigation."

IACUC

A committee, organized at every research facility subject to the AWA, PHS Policy, or AAALAC accreditation, which must review and approve or deny every proposed animal protocol.Each animal protocol must include: —A justification for using animals, the number of animals to be used, and the species chosen —The procedures or drugs to be used to eliminate or minimize pain and discomfort —A description of the methods and sources used to search for alternative to painful procedures —A description of the search used to ensure that the experiment does not unnecessarily duplicate previous research Members must include: a veterinarian, a professional not involved in research (ethicist, lawyer, etc.), and a community representative (clergy, teacher, etc.).IACUC members must inspect their research facility twice a year.

dietary supplement

A dietary supplement is a product taken by mouth that is intended to supplement the diet and that contains one or more "dietary ingredients" the "dietary ingredients" in these products may include ◦Vitamins ◦Minerals ◦Herbs or other botanicals ◦Amino acids ◦Other substances found in the human diet, such as enzymes

sponsor-investogator

An individual who both initiates and conducts a clinical investigation, and the drug is administered/dispensed under their direction

injunction

An order by a court that requires an individual or corporation to do or refrain from doing a specific act. FDA may seek injunctions against individuals and/or corporations to prevent them from violating or causing violations of the Act

patient safety in CF clinical trials - after enrollment: data safety monitoring board (DSMB)

CF experts from the DSMB monitor all study data and take action if a safety risk is found

patient safety in CF clinical trials - before enrollment: data safety monitoring board (DSMB)

CF experts from the DSMB review safety data and make a plan to monitor safety during study

patient safety in CF clinical trials - before enrollment: therapeutics development network (TDN) scientific review

CF research experts from the TDN and community representatives assess the merit of the study drug, study design and safety

patient safety in CF clinical trials - after enrollment: therapeutics development network (TDN) study oversight

CF researchers from the TDN rely on the DSMB to monitor the study

pre-IND meeting

Can reduce the application process time and time to market •Avoid premature submission of INDs •Avoid unnecessary nonclinical studies •Resolve potential safety issues •Discuss the contents of the IND and overall drug development plan •Provide regulatory guidance and answer appropriate questions

CDER

Center for Drug Evaluation and Research •Key Offices- •Generic drugs •New drugs- separated into offices based on system (cardiology, immunology, infectious diseases, etc.) •Nonprescription drugs

protocol(s)

Clinical, how often people are dosed, how often people are observed, when does it shut down

commercial speech

Commercial speech- promotional activities by product sellers is governed by Central Hudson test

module 1

Cover letter form 1571 - IND application clinical trials certification references fast track or other designation requests other correspondence general investigational plan investigator's brochure labeling

device

Device: an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component part or accessory Intended to diagnose or treat diseases Notice: similar wording to "drug" definition

what are the objectives of non-clinical tests

Does this molecule/compound work? (efficacy assessment) How can we deliver it to the right cells/tissues/organs? (toxicology/safety, pharmacology assessment) Is it safe? Can we manufacture it? (CMC activities) Ensuring safety, practicality, stability? Non-clinical development studies and activities continue throughout the life-cycle of the product identify which candidate compound has the greatest probability of success assess its safety, and build a solid scientific foundation before transition to the clinical development phase, i.e. phase I (first-in-human)

what products, articles does the FDA regulate

Drugs OTC Prescriptions Biologics/Vaccinations Food Dietary Supplements Cosmetics Tobacco Devices

amendments to FDCA

Durham-Humphrey amendment of 1951 Kefauver-Harris amendment of 1962 orphan drug act of 1983 drug price competition and patent restoration act 1984 - Waxman Hatch amendment

example of Kefauver-Harris amendment of 1962 before act

European reports of birth defects related to thalidomide, a drug about to be introduced in the US, stressed the need for additional regulation. Many drugs on market were not safe for use, except under medical supervision These drugs could not meet "adequate directions for use" requirement Drugs labeled by manuf. with "Caution: Federal law prohibits dispensing without a prescription" are exempt from labeling requirement directing "adequate directions for use" Labels on Rx drugs do not contain directions on how to use the product

what does the FDA administer (background)

FDA administers the federal FDCA

what does the FDA focus on regulating

FDA focuses on regulating manufacturers of food, drugs, and cosmetics. it does not regulate the practice of pharmacy - unless pharmacist venture into drug manufacturing more concerned about manufacturing drugs for many pharmacies rather than the compounding of drugs

patient safety in CF clinical trials - before enrollment: FDA

FDA provides guidelines for study supervision, reviews previous studies to assess safety and approves drug to be tested in humans

patient safety in CF clinical trials - after enrollment: FDA

FDA receives ongoing notification from sponsor about the safety of the study and provides federal oversight

starting phase 1 trial

FDA will give notice before you can begin Must report to FDA suspected fatal or serious adverse reactions (within 7 days after researchers receive receipt of notification) Report other serious or significant issues Annual progress reports

NDA review

FDA's New Drug Application (NDA) review

post-marketing

FDA's post-approval risk assessment systems

what agencies are responsible for drug advertising

FDA- regulates prescription drug advertising under the FDCA (15 U.S.C. § 352(n) Federal Trade Commission (in collaboration with FDA) regulates nonprescription drugs under the Federal Trade Commission Act (15 U.S.C.§ 45)

what do you do once you develop a new molecular entity

Have to prove safety and efficacy •Preclinical data- animal testing and models •IND- Investigational new drug application- clinical trials •Chemistry, manufacturing, and controls information •Clinical protocols and investigator information

what happens between the pre-clinical and clinical phase

IND review - FDA reviews the IND to assume that the proposed studies generally referred to as clinical trials do not place human subjects at unreasonable risk of harm. FDA also verifies that there are adequate informed consent and human subject protections

patient safety in CF clinical trials - after enrollment: institutional review board (IRB)

IRB at the research site provides general oversight and monitoring during the study

patient safety in CF clinical trials - before enrollment: institutional review board (IRB)

IRB at the research site reviews the study to evaluate possible benefits and risks

what was it like prior to the Durham-Humphrey amendment of 1951

Many drugs on market were not safe for use, except under medical supervision These drugs could not meet "adequate directions for use" requirement Drugs labeled by manuf. with "Caution: Federal law prohibits dispensing without a prescription" are exempt from labeling requirement directing "adequate directions for use"

AAALAC international

Nonprofit organization that accredits research facilities for compliance with the Guide.Accreditation is on a voluntary basis only.Announced site visits are conducted every 3 years.

OTC vs Rx

OTC - don't need prescription, a drug, can get anywhere, self-diagnose Rx drug - need prescription, a drug, can get only from pharmacy or prescriber, must be diagnosed by someone

what happens leading up to clinical trials

Observational studies and/or prospective pilot studies help inform scientific questions and hypotheses for future clinical trials, including RCTs

who evaluates the IND

Office of New Drugs (OND) within the Center for Drug Evaluation and Research (CDER) CDER evaluates OTC and prescription drugs IRB- Reviews studies and informed consent of participants Clinical trial protocols Schedule of tests and procedures Medications and dosages Length of the study Study objectives

phase 3

Only 9% of drugs make it to phase 3 Pivotal trial period Requires adequate and well-controlled investigations Submit at least 2 trials providing independent evidence of efficacy Clinical endpoints? Any additional concerns for diabetic patients in this example? Why at least two? May allow one for an extremely rare condition

NDA user fees

PDUFA- pay to play Support timely review Options for waivers/reduction/refunds Applicable here- small business, first time applicant

what does it take to do an RCT

People - investigators, study staff, any people supporting you in clinical trial Money - millions of dollars for one trial Time - takes from months to years

Right to Try Act (states)

Permits/allows eligible patients to have access to eligible investigational drugs. •An eligible patient is a patient who has: -Been diagnosed with a life-threatening disease or condition -Exhausted approved treatment options and is unable to participate in a clinical trial involving the eligible investigational drug (this must be certified by a physician who is in good standing with their licensing organization or board and who will not be compensated directly by the manufacturer for certifying) -And has provided, or their legally authorized representative has provided written informed consent regarding the eligible investigational drug to the treating physician

what does pharmacodynamic and pharmacokinetic help us explain

Pharmacodynamics and pharmacokinetics helps explain the relationship between the does and response, i.e., the drug's effects The pharmacologic response depends on the drug binding to its target. The concentration of the drug at the receptor site influences the drug's effect

healthy volunteers

Phase I studies, usually adults

why IND has specific content information

Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans. Also included are any previous experience with the drug in humans (often foreign use). Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product. This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug. Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks. Also, information on the qualifications of clinical investigators--professionals (generally physicians) who oversee the administration of the experimental compound--to assess whether they are qualified to fulfill their clinical trial duties. Finally, commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations.

private parties

Private parties: Lanham Trademark Act (15 U.S.C. § 1125) allows private parties a cause of action against false and misleading advertising- at that state level most pharmacy practice acts prohibit pharmacists from false, misleading or deceptive advertising. A.R.S. § 32-1901.01(A)(29)

PHS policy

Protects all vertebrate animals (including fish, reptiles, rats, mice, and birds) used in research funded by the Public Health Service. Each research facility provides a written plan for complying with PHS Policy and the Guide. Each research institution that receives PHS funding must have the IACUC review all animal experimental protocols and inspect the facilities.No routine, unannounced inspections, but all allegations of misuse are investigated by NIH's Office of Laboratory Animal Welfare.Violations or loss of AAALAC accreditation can result in loss of PHS funding.

animal welfare act

Protects all warm-blooded animals except rats, mice, and birds bred for research. This includes zoos, circuses, research labs, hospitals, businesses, federal agencies, dealers, breeders, etc. Each research institution that uses a covered species must have an IACUC review all animal experiment protocols. The USDA licenses research facilities and conducts annual, unannounced inspections. Violations are punished with fines, cease-and-desist orders, and license suspension or revocation.

class I recall

Reasonable probability that the use of, or exposure to, a violative product with cause serious adverse health consequences or death

recall

Recall- the correction or removal, and notification to the company, of a product that is in violation of the law. Three levels of recall

phase 3 reporting

Safety reports Annual report Pre- NDA meeting

post approval

Safety reports Post market studies or clinical trials

As citizen, scientist, health care provider, what information do you want in the NDA?

SAFETY AND EFFICACY BENEFITS/RISKS What should be on drug label Manufacturing process- quality

how does the FDA review

Standard 12 months Priority 8 months Demonstrate drug or biologic has potential to significantly improve safety or effectiveness of treatment, diagnosis, prevention of serious/life threatening condition

starting phase 2

Submit protocol Begin trials Safety and efficacy patient dose ranging comparison to

OODP

The FDA Office of Orphan Products Development (OOPD) mission is to advance the evaluation and development of products (drugs, biologics, devices, or medical foods) that demonstrate promise for the diagnosis and/or treatment of rare diseases or condition

1906 pure food and drug act rationale

The Jungle - problems in the meat processing industry Fraudulent patent medications containing dangerous substances like alcohol, cocaine, morphine, opium advertised as cure

application information on an IND

The amount of information that must be submitted is determined by •Novelty of the drug •Extent of previous study •Known or suspected risks •Developmental phase of the drug •Sponsors should use their discretion to determine information to be submitted.

what is the main difference between a commercial and research IND

The main difference is who submits the application to FDA and the intended purpose of their clinical research.

sponsor

The person who takes responsibility for and initiates a clinical investigation (pharmaceutical company, private/academic organization, or an individual).

what is the importance of developmental toxicity and carcinogenicity data vs clinical data

The relative importance and reliance on non-clinical developmental toxicity and carcinogenicity data for human safety. Data from developmental toxicity studies and carcinogenicity studies continue to be relied upon more than clinical data throughout development and after marketing authorization

what is the relevance of non-clinical studies in medicines development

The relative importance of and reliance on non-clinical data in the medicines development process over time. Data from non-clinical studies are relied on more than clinical data until later in the development process

drug advertisement target audience

To health care professionals To end users (consumers)

pre-phase 3

Up to this point: established biological activity, begun to establish safety profile, documented preliminary efficacy Submit a packet to FDA- phase 3 protocols, summary of phase 1 and 2 investigations, pediatric study plan

class III recall

Use of or exposure to the product is not likely to cause serious adverse health consequences

class II recall

Use of or exposure to the product may cause a temporary or medically reversible adverse health consequence, or where the probability of serious health consequences is remote

how do patents work

When a drug is under patent protection, the company markets it under its brand name. When the drug is off-patent (no longer protected by patent), the company may market its product under either the generic name or brand name. Other companies that file for approval to market the off-patent drug must use the same generic name but can create their own brand name. As a result, the same generic drug may be sold under either the generic name (for example, ibuprofen) or one of many brand names (such as Advil or Motrin).

FDA court

Within 60 days- notification of completeness Information requests More data, conduct alternative analyses, clarifications Finalize package insert/labeling Inspection of clinical sites May convene an advisory committee Review results Approval letter Complete response letter- not approved- defect to be resolved

full clinical hold

a delay or suspension of all clinical study under an IND

partial clinical hold

a delay or suspension of only part of the clinical study under an IND (e.g., a specific protocol or part of a protocol is allowed to proceed)

who reviews new drug submissions

a team of CDER physicians, statisticians, chemists, pharmacologists, and other scientists review the drug sponsor's data and proposed labeling of drugs

warning letters

are sent to the individuals or firms, advising them of specific noted violations.; These letters request a written response as to the steps which will be taken to correct the violation. These letters constitute one form of warning that can be issued under current Agency policy

safety pharmacology core studies

assessing effects on cardiovascular, respiratory, and central nervous systems (CNS)

generics approval applications

abbreviated new drug application (ANDA) supplemental new drug applications (SNDA)

-prazole

acid reducer

emergency use IND

allows the FDA to authorize use of an experimental drug in an emergency

standard new drug application approval pathway

an application containing full reports of investigations of safety and effectiveness conducted by the applicant

rapid new drug application approval pathway

an application containing full reports of investigations of safety and effectiveness. but some of the information required for approval is obtained from studies conducted by other entities for drugs already approved by the FDA

abbreviated new drug application (ANDA) (for generics)

an application containing information that shows the proposed product- a generic form of an existing drug - is as equally safe and effective as the existing drug

clinical hold

an order issued by FDA to the sponsor of an IND to delay a proposed a clinical investigation or suspend an ongoing clinical investigation

-azepam

anti-anxiety

-coxib

anti-inflammatory

-oxetine

antidepressants

-vir

antivirals

generic

assigned by United States Adopted Names (USAN)

-lukast

asthma

what does FDA regulate

biologics - products and manufacturing, safety of US blood supply cosmetics drugs food, labeling, safety of food products (except meat and poultry) medical devices radiation emitting electronic products; microwares, TV receivers, X-ray equipment, laser products, mammography facilities veterinary products - feed, pet food, veterinary drugs and devices tobacco

-sartan

blood pressure lowering

investigational plan

brief description of the overall plan for investigation summary of rationale to support trial dose, dosing schedule, patient population indication(s) trial duration/number of subjects known risks (based on toxicology)

module 3 - quality

chemistry, manufacturing, and controls drug substance drug product certificates of analysis placebo formulation description of drug product/drug substance form non-IND foreign clinical studies

-vastatin

cholesterol lowering

pharmacology and toxicology information

clinical data that shows drug is reasonably safe to test in humans

what are the two IND catagories

commercial research (non-commercial)

sources of law

constitution statutes regulations

clinicians should always

critically evaluate studies when considering them in application to clinical practice

pharmacokinetics and toxicokinetics studies

data gathered during in vitro studies on metabolic and blood protein binding data for animals and humans. systemic exposure data from toxicology studies

IND process from day 1-30

day 0-7: receipt and assignment of reviewers day 8-27: review and safety meetings day 25-30: safety decision and notifications

chemical name

describes atomic or molecular structure

brand

developed by the company requesting approval for the drug identifies it as the exclusive property of that company

-formin/glitazone

diabetes

Durham-Humphrey amendment of 1951

distinguishes prescription from non-prescription Before: all drugs were OTC created: prescription drugs required: prescription drugs to contain a warning that the drugs could be dispensed legally only with the authorization of a health professional (legend)(caution federal law prohibits dispensing w/o prescription) made it so you needed prescription to get drug

patient safety in CF clinical trials - before enrollment: site study team

doctor at the research site reviews your health to see if you can safely participate in the study

steps in pre-clinical

drug developed - drug sponsor develops a new drug compound and seeks to have it approved by FDA for sale in the US animals tested - sponsor must test new drug on animals for toxicity. multiple species are used to gather basic information on the safety and efficacy of the compound being investigated/researched IND application - the sponsor submits an Investigational New Drug (IND) application to FDA based on the results from initial testing that include the drug's composition and manufacturing and develops a plan for testing the drug on humans

clinical phase

drug sponsor's clinical studies/trials

pre-clinical

drug sponsor's discovery and screening phase

legend drug

drug that, by law, can be obtained only by prescription and bears the label "Caution: Federal law prohibits dispensing w/o a prescription" but nowadays the label simply states "RX only" labels on Rx drugs do not contain directions on how to use the product says who can't possess it and who can have it

what other products are regulated by FDA

drugs include more than just medicines. for example, fluoride toothpastes, antiperspirants (not deodorant), dandruff shampoos, sunscreens are all considered drugs

Orphan drug act of 1983

drugs intended to treat rare diseases and conditions may be designated "orphan drugs" which provides pharmaceutical manufacturers tax and licensing incentives to develop them. gives manufactures incentives to make the drug for the small group of people that will constantly need that drug to live

module 2 -summaries

electronic common technical document (eCTD) introduction to summary quality overall summary nonclinical overview clinical overview nonclinical written and tabulated summaries clinical summaries

-afile

erectile disfunction

what are the different expedited reviews

fast track designation breakthrough therapy designation accelerated approval pathway priority review designation

other studies of concern

for instance, investigation into phototoxicity (causing a reaction of the skin when exposed to light)

vaccinations

great benefit to society as a whole, but potential for higher individual (personal) cost- acute reactions, injection pain Orphan drugs- open market doesn't make it efficient or feasible to produce drugs that treat a condition with relatively small numbers of sufferers

study participants in RCTs

healthy volunteers participants w/ disease/condition for which intervention is being studied success in study participant enrollment depends on various factors Rarer disease makes it hard to get volunteers If patient is harm you lose trust and hurts volunteers later

example of drug before 1938 act

in 1937, nearly 100 people died after ingesting Elixir Sulfanilamide which had been prepared using diethylene glycol company didn't label the product appropriately and didn't test for safety

patient safety in CF clinical trials - before enrollment: patient's role

in the informed consent process, you are given all the available information about the study plan as well as possible risks and benefits, and your questions are answered

types of non-clinical studies

in-vitro in-vivo in-silico

what content is on an IND

introductory statement general investigational plan investigator's brochure protocol(s) chemistry, manufacturing, and control data pharmacology and toxicology information previous human experience additional information (drug, dependence, abuse potential, radioactive, pediatric studies) relevant information (foreign, previously submitted)

IND

investigational new drug application

types of toxicity studies

local tolerance studies genotoxicity studies carcinogenicity studies reproduction toxicity studies

modules of an IND

module 1 - administrative information module 2 - summaries module 3 - quality module 4 - nonclinical study reports module 5 - clinical study reports

Kefauver-Harris Amendment of 1962

new authorities given to FDA by Kefauver-Harris amendment

what was drug regulation like in the past

no safety in the past, many things were harmful and is why we don't do those things today no science or trials behind drugs, did want to make them feel better, just needed aid to get drug

orphan drugs

open market doesn't make it efficient or feasible to produce drugs that treat a condition with relatively small numbers of sufferers. Vaccinations- great benefit to society as a whole, but potential for higher individual (personal) cost- Orphan drugs- open market doesn't make it efficient or feasible to produce drugs that treat a condition with relatively small numbers of sufferers. Vaccine and Orphan drugs- open market doesn't make it efficient or feasible to produce drugs that treat a condition with relatively small numbers of sufferers.

introductory statement

orientation

application format

paper (research applications only) - common technical document (CTD) format; regulatory format electronic - must use eCTD format; physical media; electronic submission gateway

types of non-clinical studies/categories

pharmacodynamics studies pharmacokinetics studies

what are the phases of the clinical phase

phase 1 - 20-80; typical number of healthy volunteers used in phase 1; this phase emphasizes safety. the goal here in this phase is to determine what the drug's most frequent side effects are and often how the drug is most metabolized and excreted phase 2 - 100s; the typical number of patients used in phase 2; this phase emphasizes effectiveness. this goal is to obtain preliminary data on whether the drug works in people who have a certain disease or condition. for controlled trials, patients receiving the drug are compared with similar patients receiving a different treatment-usually a placebo or a different drug. safety continues to be evaluated and short-term side effects are studied at the end of phase 2, FDA and sponsors discuss how large-scale studies in phase 3 will be done phase 3 - 1000's; the typical number of patients used in phase 3; these studies gather more information about safety and effectiveness, study different populations and different dosages and use the drug in combination with other drugs

post-marketing phases

phase 4 - b/c it's not possible to predict all of a drug's effects during clinical trials, monitoring safety issues after drugs get on the market is critical. the role of FDA's post-marketing safety system is to detect serious unexpected adverse events and take definitive action when needed once FDA approves a drug, the post-marketing monitoring stage begins. the sponsor (typically the manufacturer) is required to submit periodic safety updates to FDA FDA's MedWatch voluntary system makes it easier for physicians and consumers to report adverse events. usually, when important risks are uncovered the risks are added to the drug's labeling and public is informed of new info through PSA

drug development funnel

potential new drugs: tens of thousands (3-6 years) drug discovery nonclinical studies 6-7 years clinical trials 6-12 months FDA review as drugs travel through the funnel, their number decreases as studies indicate problems with safety and/or effectiveness

phases of FDA drug approval process

pre-clinical clinical NDA review post-marketing

drug advertising and promotion

private parties first amendment right to free speech commercial speech Speech must not be misleading or related to unlawful activity Government interest in the regulation must be substantial Regulation must directly advance the governmental interest asserted The restriction cannot be more extensive than necessary to serve the interest Drug advertising is commercial speech, so questions are what advertising, what manner, and to what extent

1906 pure food and drug act purpose

prohibited marketing of adulterated (contaminated) and misbranded food and drugs

sufficient CMC information

proper identification of the substance quality of the substance purity of the substance strength of the substance

rationale for regulating medications - why do we regulate medications/drugs

public good externalities natural monopolies information asymmetry

federal food, drug, and cosmetic act of 1938

required manufacturers demonstrate safety of new drugs prior to marketing allowed FDA to inspect manufacturing facilities allowed FDA to enforce through injuctions defined the following key terms: drug, device, cosmetics and labeling

RCTs are

resource intensive and complex

what is the FDA responsible for

responsible for regulating all aspects of the manufacturing and, to a lesser extent, wholesale distribution of prescription and non-prescription drugs

NDA review steps

review meeting - FDA meets with a drug sponsor prior to submission of a NDA NDA application - drug sponsor formally asks FDA to approve a drug for marketing in the US by submitting an NDA. An NDA includes all animal and human data and analyses of the data, as well as information about how the drug behaves in the body and how it is manufactured application reviewed - after an NDA is received, FDA has 60 days to decide whether to file it so it can be reviewed. if FDA files the NDA, the FDA review team is assigned to evaluate the sponsor's research on the drug's safety and effectiveness drug labeling - FDA reviews the drug's professional labeling and assures appropriate information is communicated to health care professionals and consumers facility inspection - FDA inspects the facilities where the drug will be manufactured

what toxicity studies are required before clinical testing

safety pharmacology core studies primary pharmacodynamic studies pharmacokinetics and toxicokinetics studies acute toxicity studies repeated-dose toxicity studies other studies of concern

screening (of participants)

screening process

removing drugs from the market

seizure recall

what are the two mechanisms to remove drugs from the market

seizure and recall

acute toxicity studies

single-dose toxicity studies in two mammalian species - but can be completed during studies that define a maximum tolerated dose in the species used for toxicity testing

patient safety in CF clinical trials - before enrollment: study sponsor

sponsor develops a study plan (protocol), which includes a guide for how safety will be monitored

patient safety in CF clinical trials - after enrollment: study sponsor

sponsor's medical expert reviews adverse events in real time

form FDA 1572

statement of investigator - form FDA 1572 - statement of the investigator conducting clinical research under IND -requirements to have investigator(s) sign before participation -provides clinical investor qualifications -agreements: conduct of protocol; obtain informed consent; institutional review board (IRB) review; recordkeeping, adverse drug reactions

patient safety in CF clinical trials - after enrollment: site study team

study doctor and research coordinator monitor your health during the study and can pull you out of the study if your health is a concern

statutes

•Statutes- laws created by legislatures •US •State

GATT

term of a patent is 20 years patent - when main drug is about to renew their patent, other drug companies will try to submit their before the main one is approved

faster approvals - accelerated approval program

the Accelerated Approval program allows earlier approval of drugs that treat serious diseases that fit an unmet medical need. the approval is faster b/c FDA can base the drug's effectiveness on a "endpoint" such as a blood test or X-ray result rather than waiting for results from a clinical trial

when and how was the FDA created

the FDA as a scientific institution dates from 1862 when Charles M. Wetherill, first chemist of the new Department of Agriculture, set up a laboratory and began to analyze samples of food, soils, fertilizers, and other agricultural substances

faster approvals - fast track

the Fast Track program helps reduce the time for FDA's review of products that treat serious or life-threatening diseases and those that have the potential to address an unmet medical need. drug sponsors can submit portions of an application as the information becomes available; makes process faster than waiting until all information is available

label

the display of written printed or graphic matter upon the immediate container and or wrapper drug name, established name - generic/chemical; strength, quantity, recommended dosage, lot number, Rx statement, expiration date

labeling

the label AND any accompanying information like package insert, the patient package insert, or other materials Highlights, boxed warning (if required), indications and usage, dosage and administration, dosage forms and strengths, contraindications, warnings and precautions, adverse reactions, drug interactions, use in specific populations, drug abuse and dependence, over dosage Labeling - is the label and printed material with the drug Label - is just the thing on the outside (first picture)

1906 pure food and drug act problem

there products were subject to seizure by the government but the law didn't limit the claims a manufacturer could make regarding their product as long as the product was correctly identified. and the law didn't require pre-market approval

what does this tell you about drug approval process

time consuming (almost a decade) costly strategic planning

why do we regulate drug, devices, food, cosmetics

to know they are safe for consumers

repeated-dose toxicity studies

vary in length according to duration, therapeutic indication and scope of the proposed clinical programme. minimum duration for two weeks in two species (one of which is not a rodent)

FDA enforcement actions

warning letters seizure injunction criminal prosecution

chemistry, manufacturing, and control data

what is ingredients in active drug product, shelf stability, binding, how its manufactured, what is placebo, is placebo easily identified

patient safety in CF clinical trials - after enrollment: patient's role

you follow the study plan as explained during the consent process and you keep your physician informed about how you're feeling and any concerns you have

seizure for removing drugs from market

§Seizure- the physical isolation of a drug while FDA or state agency files civil lawsuit § FDA can seize drugs that are "misbranded" or "adulterated" §Product Recalls- FDA has authority or manufacturer can voluntarily recall; manufacturer responsible for contacting consumers. PHARMACIST responsible for knowing which drug products have been recalled. Pharm publications often list; available on FDA site

questions that must be addressed in the use of animals in medicines research and development

• How applicable are animal models for the human situation? •Were the non-clinical signs and pathologies sufficiently studied within the context of the proposed human use of the novel medicine? •Risk vs. benefit

what is an RCT

•A prospective, comparative, quantitative study, or experiment performed under controlled conditions with random allocation of interventions to comparison groups • •Rigorous and robust -> considered "high quality evidence" • •Helps answer the question of whether or not a cause and effect relation exist between an intervention and an outcome

informed consent and assent - what is common rule

•A regulation governing the use of human subjects in federal research

looking beyond the face value of RCTs

•A singular RCT usually should/does not define a clinical practice approach • •Need to critically evaluate each RCT •Design •Study population •Statistical analysis •Assess for bias, confounders • •RCTs are valuable but only if done correctly!

pharmacokinetic studies

•Aim to study the effects of the body on the medicine •ADME: A (absorption), D (distribution), M (metabolism), E (excretion) • Toxicokinetics - is the product toxic? (what the body does to a drug, or the fate of a drug within the body [1-2]),

compose a multidisciplinary DMC

•All members reviewed for possible conflicts of interest

expanded access requirements

•All three types of expanded access programs must meet the following three basic criteria: -Presence of a serious or life-threatening condition -No comparable alternative treatment -Patient enrollment in a clinical trial isn't possible -Potential benefit to patient justifies the risk -Use of the IND will not interfere with its clinical investigative process or compromise its development

clinical investigation/clinical trial

•Any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects.

genotoxicity studies

•Assessment of gene mutation •Assessment for chromosomal damage in mammalian systems •If positive findings are observed in genotoxicity tests, additional testing must be considered.

when are RCTs considered

•Based on previous data •e.g., animal studies, observational studies, smaller RCT pilot • •Evaluate the effectiveness or safety of one or more interventions (most common) • •Evaluate the effectiveness or safety of one or more diagnostic or screening tests • •When gaps in evidence are identified when developing guidelines

development of the compound for its use in development

•Before non-clinical studies can begin, an adequate amount of the active ingredient (AI) must be produced. •Non-clinical studies usually require quantities of the AI in milligrams or grams; later stages of the development process will require a scale-up process to produce kilograms of the AI

chemistry, manufacturing, control (CMC)

•Chemistry, Manufacturing, Control (CMC) are key aspects during non-clinical development. Chemistry, Manufacturing, Control (CMC) - key aspects during non-clinical development Chemistry, Manufacturing, Control (CMC) are key aspects during this process All non-clinical development studies necessitate manufacture of an adequate active ingredient: quantities of milligrams to grams are usually needed for non-development studies; then a scale-up process must be developed to produce kilograms. For Good Laboratory Practice (GLP) studies, qualified or Good Manufacturing Practice (GMP) batches of the active substance are required

challenges of clinical trials

•Cost - time, resources, financial • •Study participant enrollment • •Study team and/or site oversight / management • Investigators are often divided in their time and attention Pediatric volunteers are hard to obtain b/c of parent consent Time zones are challenging and there are different practices at each center of study

data collection, retention, and monitoring

•Data collection instruments •Data management procedures •Quality assurance and performance measuring •Security Data and Monitoring •Data Sharing

administrative, ethical, and regulatory considerations

•Declaration of Helsinki, Protection of Human Volunteeres •Protocol amendments •IRB and Independent Ethics Commitees •Informed Consent •Publications •Responsibilities of investigator

protocol violations

•Definitions •What do to in case of

develop charter between DMC and trial sponsor

•Describes structure and operation of the DMC for a given trial

study intervention(s)

•Description of intervention(s) •Method of assigning participants to study groups (e.g., randomization) •Blinding (if applicable)

criteria for evaluation

•Details about study measures, definitions

non-clinical outcomes that can stop development

•Discovery of target organ toxicity •For example, if a compound is hepatotoxic (toxic for the liver) in an animal •Identification of poor pharmacokinetic properties •For example, if a product is poorly absorbed, if it accumulates, or if it generates toxic metabolites. •ADME studies are performed to optimize selection of successful product candidates

steps towards an RCT: preparation

•Do your homework - previous studies •Strengths and weakness? • •Do you have pilot data? • •Is it of value (clinical, social, or economic)? • •Is it feasible given your available resources? • •Develop the research question (hypotheses) •Specific and formulated

assess safety and efficacy data

•Early termination needed? •Continuation reviews

multidisciplinary representation

•Ensure all relevant medical, ethical, safety, and scientific issues can be adequately discussed and properly weighed in all recommendations concerning trial conduct and termination •Example: Cystic Fibrosis Foundation Therapeutic Development Network, Data Safety Monitoring Board (DSMB) •Physicians, psychologist, pharmacists, biostatisticians, patient/family members, etc.

participant selection

•Exclusion and Inclusion Criteria - make sure no bias or confounding factors in trials •Study specific tolerance for inclusion/exclusion criteria •Screen fail criteria

assent

•Expresses willingness to participate in research by persons who are by definition too young to give informed consent, usually applies to minors (often age 9 years and older) •Not sufficient alone • •Much simpler document, sometimes verbal • •Participant is old enough to understand the proposed research in general, its expected risks and possible benefits, and the activities expected of them as subject Verbal assent is simplifying for child to understand and the child verbally agreeing to study

what does the FDA inspect

•FDA inspects manufacturers or processors of FDA-regulated products to verify that they comply with relevant regulations. Those inspected include- vaccine and drug manufacturers, blood banks, food processing facilities, dairy farms, animal feed processors, compounding pharmacies •FDA also inspects - facilities that conduct studies in people (clinical trials), laboratories that conduct studies in animals or microorganisms when these studies are used to apply for FDA approval of a medical product, foreign manufacturing and processing sites for FDA-regulated products that are sold in the United States, imported regulated products at the border •FDA conducts several types of inspections to help protect consumers from unsafe products: •pre-approval inspection after a company submits an application to FDA to market a new product •routine inspection of a regulated facility •"for-cause" inspection to investigate a specific problem that has come to FDA's attention

carcinogenicity studies

•For medicines indicated for serious diseases in adults or pediatric patients, carcinogenicity testing may be concluded post-approval based on the assumption that early access to the medicines for patients outweighs the possible risk, but the sooner these can be carried out the better.

initial review

•Study protocol, manual of procedures •Data management and quality control procedures

right to try act - an eligible investigational drug is an investigational drug

•For which a Phase 1 clinical trial has been completed •That has not been approved or licensed by the FDA for any use •For which an application has been filed with the FDA or is under investigation in a clinical trial that is intended to form the primary basis of a claim of effectiveness in support of FDA approval and is the subject of an active investigational new drug application submitted to the FDA •Whose active development or production is ongoing, and that has not been discontinued by the manufacturer or placed on clinical hold by the FDA

what are the key CMC steps during non-clinical development

•Formulation for non-clinical development studies •Determining the dosing system and method of application of the active ingredient based on product properties and type of animal model. •Detailed physical chemistry characterization •Stability testing and impurity analysis •Development and validation of methods to quantify the active substance in body fluids (e.g. blood, plasma, urine) in pharmacokinetic and toxico-kinetic studies Development of a prototype for the clinical formulation

how do you get money for RCT

•Funding from various sources • •Intramural funding •University/College/Department grants •Faculty start up funds • •Extramural funding •Federal agency (e.g., NIH) •Foundation •Industry • •GRANTSMANSHIP = skill (and art) improved with time and experience

unique IND situations

•IND using an approved drug •IND using a foreign marketed drug •IND using a compendia drug •IND referencing drug master file (DMF) or existing IND or NDA for CMC information -Need a letter of authorization from the originally submitting entity An IND that is a marketed, approved product distributed by an NDA applicant CMC information may be minimal because the quality has already been evaluated in the NDA or ANDA The specific information to provide when using a marketed approved, or unapproved product in an IND will be discussed in this course

what does OODP evaluate

•In fulfilling that task, OOPD evaluates scientific and clinical data submissions from sponsors to identify and designate products as promising for rare diseases and to further advance scientific development of such promising medical products. The office also works on rare disease issues with the medical and research communities, professional organizations, academia, governmental agencies, industry, and rare disease patient groups.

how do studies meet Good Laboratory Practice (GLP) guidelines

•In order for studies to meet Good Laboratory Practice (GLP) guidelines, the batches of AI must be qualified and produced according to Good Manufacturing Practice (GMP) guidelines.

in-silico

•In-silico (pseudo Latin) an expression meaning 'performed on computer or via computer simulation'; for example, predicting the toxicology profile of a product using its chemical structure with data-based approaches In silico (e.g. computer models) pharmacogenomics effects on biomarkers development of the compound

in-vitro

•In-vitro (Latin for 'within the glass') •performing a procedure in a controlled environment outside of a living organism; for example, using cancer cell cultures (does the molecule stop cancer cells from growing). e.g. cell lines of a tumor

in-vivo

•In-vivo (Latin for 'within the living') •experimentation using a whole, living organism as opposed to tissues or cells; animal testing. In vivo studies (e.g. animal models) pharmacodynamics (effects of medicine on organism) pharmacokinetics (effects of organism on medicine) toxicity (toxicology) effects on pregnancy and fertility carcinogenicity

why are non-clinical studies necessary

•Information obtained in non-clinical studies is needed for decisions: •on clinical trials, •on IND applications, and •on post-marketing or monitoring studies. •Non-clinical information is also used •To determine human dosing •In safety monitoring

informed consent and assent - informed consent is part of common rule requirements

•Informed consent forms will have text at the top of the form that provides key information about the study •Includes a statement about whether and when clinically relevant research results will be shared with subjects

what is a major consideration as part of RCT development

•Informed consent(and assent) is important and a major consideration as part of RCT development

informed consent and assent - why is it called "informed" consent and assent

•Informs participants about key elements of a research study and what their participation will involve

participants w/ disease/condition for which intervention is being studied

•Initially: adults (18 years+) vs. age 12 years and older •Later on: younger populations •PK studies •Safety and efficacy studies

natural and role of law in society what is the law and the legal system

•Laws must be clear and firm, but flexible enough to accommodate different individuals and circumstances •Referees or umpires •Balancing of individual rights and freedoms with societal concerns/protecting the public's safety or health ○Includes the rules and regulations- the what you can and cannot do ○But, also the framework through which people in society resolve disputes and problems

how do sources of law interact

•Legislature writes statute •Agency proposes and then promulgates regulations as directed by statute; investigates and enforces regulatory violations •Court interprets a statute or a regulation; may hold a statute unconstitutional •A higher court may overrule a lower court decision •Or direct a lower court to reconsider an issue

who are part of a DMC

•Members need to be free of significant conflicts of interest related to studies to be reviewed - members can't be speakers for competing drug companies multidisciplinary representation

pharmacodynamics studies

•Method of action vs. mode of action •Mechanism- biochemical interaction through which a drug substance produces a pharmacological effect •Mode- describes functional or anatomical changes, at the cellular level resulting from the exposure of a living organism to a substance - action on specific receptors or enzymes (sometimes described as what a drug does to the body) is the study of the biochemical, physiologic, and molecular effects binding (including receptor sensitivity), postreceptor effects, and chemical interactions. Pharmacokinetics (what the body does to a drug, or the fate of a drug within the body [1-2]),

what is a clinical trial

•NIH definition of clinical trial: "a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes" • •Clinical trials can include interventions that may not necessarily be a drug compound •Example: adherence research (behavioral intervention)

when is an RCT least appropriate

•Not for investigating the etiology or natural history of disease • •When outcomes are rare and/or take a very long time (e.g., years) to develop • •Questionable or lack of social value (not ethical) • •Intervention has major safety issues (risk > benefit)

what does OODP provide

•OOPD provides incentives for sponsors to develop products for rare diseases. The program has successfully enabled the development and marketing of over 600 drugs and biologic products for rare diseases since 1983. In contrast, fewer than 10 such products supported by industry came to market between 1973 and 1983. •The Orphan Grants Program has been used to bring more than 60 products to marketing approval. The Humanitarian Use Device Program has been the first step in approval of 70 Humanitarian Device Exemption approvals.

study design

•Overview •Schematics of study/clinic visits, what's happening, what's measured

USANC rules

•Prefixes that imply 'better,' 'newer,' or 'more effective;' prefixes that evoke the name of the sponsor, dosage form, duration of action or rate of drug release should not be used." •"Prefixes that refer to an anatomical connotation or medical condition are not acceptable." •Certain letters or sets of letters also aren't allowed at the beginning of new generic names. These include me, str, x, and z

what is a data monitoring committees (DMC)

•Primary responsibility: "protect the safety of trial participants, the credibility of the study and the validity of study results" • •For randomized clinical trials specifically focused on clinical efficacy and safety •Expected to provide a definitive answer to a question about whether a drug is effective than another •Less common for trials addressing symptom relief

what people do you need to do an RCT

•Principal Investigator(s) •Co-Investigator(s) •Research coordinators •Students, Fellows •Biostatistician •Investigational Pharmacist (if applicable) •Laboratory staff •Patient/Family Liaison(s) •Data Monitoring Committee

externalities

•Production or consumption of a good affects someone who does not fully consent to the effect and when the costs of a good are not fully incorporated into the price a consumer pays for it. Think antibiotic resistance or opioid addiction

what are the FDA's responsibilities

•Protecting the public health by ensuring the safety, effectiveness and security of human and veterinary drugs, medical devices, vaccines and biological products •Providing the public with accurate, science-based information to ensure the safe and appropriate use of medical products and foods •Ensuring the safety and proper labeling of food •Regulating the manufacturing, marketing, and distribution of tobacco products to protect the public health and to reduce tobacco use by minors •Protecting the public from radiation released by certain electronic products

how does an RCT reduce bias

•Randomization balances participant characteristics between groups -> attribution of any differences in outcome (most likely) to study intervention (vs. confounders)

evaluate quality of ongoing study conduct

•Rate of accrual •Compliance with eligibility restrictions, look for any imbalances

why an RCT

•Reduces bias from confounding factors •Observational design is prone to this!

regulations

•Regulations- laws created by administrative agencies •Agencies themselves are usually created by legislatures •US agencies State agencies

preparing your study protocol for RCT

•Research Question / Hypotheses • •Specific Aims •Are they each independent of each other? •Are they each feasible? •How will you achieve and/or measure each item? • •Study population - inclusion and exclusion criteria • •Study methods - the in's and out's of your study, knowing flaws and limitations

how do submissions get to the reviewers

•Review Team assigned •- Clinical •- Non-Clinical Pharmacology and Toxicology •- CMC (Chemistry, Manufacturing and Controls) •- Clinical Pharmacology •- Biostatistics •- Clinical Microbiology (Antimicrobial and antiviral •drugs) •- Microbiology-Sterility (as needed) •- Consults

statistical methods and considerations

•Sample size, randomization •Data analysis plan - analysis of primary and secondary outcomes

what scenarios to toxicology studies aim to address the toxicity of the compound in different scenarios

•Single-dose toxicity •Repeated-dose toxicity •Genotoxicity (will the product alter the genetic profile, interfering with DNA or chromosomes?) •Carcinogenicity (will the product cause cancer?) •Development and reproductive toxicity (DART)

public good

•Some drugs are public goods- there's not always an incentive for a private entity to provide them. Think about orphan drugs- vaccinations

what are examples of animal models

•Some examples of animal models include: •rat (osteoporosis, inflammatory diseases, diabetes, obesity, cardiovascular dysfunctions, neurodegenerative diseases, cancers), •monkey (osteoporosis, inflammatory diseases), •pig (cardiovascular dysfunctions such as hypertension), and •mouse (cancers and some genetic diseases)

how to choose the first-in-human dose

•Some important factors to consider when the first-in-human dose is established include: •All relevant nonclinical data •pharmacological dose response studies, •pharmacological/toxicological profile, and •pharmacokinetics studies •Particular aspects of the candidate compound, and •Clinical Study design •The No Observed Adverse Effect Level (NOAEL) is most important •NOAEL level is the level of exposure at which there is no significant increase in the frequency or severity of any adverse effects. In the case of many biotechnology-derived medicines (biological medicines), and when risk factors have been identified, the first human dose is established using the Minimal-Anticipated-Biological-Effect-Level (MABEL)

how is the FDA funded

•The FDA budget for FY 2019 was $5.7 billion. •About 55 percent, or $3.1 billion, of FDA's budget is provided by federal budget authorization. •The remaining 45 percent, or $2.6 billion, is paid for by industry user fees. •The FDA budget is equivalent to $9.63 per American per year. •The Tobacco Control Act Program is paid for entirely by industry user fees.

what are the FDA's responsibilities

•The FDA is an agency within the U.S. Department of Health and Human Services. •In addition to the 50 states, the FDA's responsibilities extend to the District of Columbia, Puerto Rico, Guam, the Virgin Islands, American Samoa, and other U.S. territories and possessions.

emergency use regarding of drug

•The emergency use of an unapproved investigational drug or biologic requires an IND. If the intended subject does not meet the criteria of an existing study protocol, or if an approved study protocol does not exist, the usual procedure is to contact the manufacturer and determine if the drug or biologic can be made available for the emergency use under the company's IND. • •Emergency use is defined as the use of an investigational drug or biological product with a human subject in a life-threatening situation in which no standard acceptable treatment is available and in which there is insufficient time to obtain IRB approval

selection process of an animal species

•The selection process of an animal species is based on the similarities between the animal species and humans in aspects such as: •pharmacodynamics (safety pharmacology), •pharmacokinetics, and •physiology and pathophysiology of the species compared: •Healthy animals can be used •As well as specific animal disease models

natural monopolies

•These occur when the fixed costs of providing a good are high relative to the variable cost so the average cost declines over the time the good is provided- think about the cost to develop a drug

study procedures and guidelines

•Timeline of study points •Procedures by study team including informed consent •Clinical assessments •Data collection •Evaluations by time point in study

how to determine if a DMC is needed

•Trial intended to provided definitive information about effectiveness and/or safety? •Prior data to suggest that the intervention has potential to induce potentially unacceptable toxicity? •Does the trial evaluate mortality or another major endpoint such that inferiority of one treatment arm has safety as well as effectiveness implications? •Ethically important for the trial to stop early if primary question addressed has been definitively answered, even if secondary questions or complete safety information were not yet fully addressed?

constitution

•US •State

informed consent

•Usually applies to adult participants • •Sufficient alone in some cases (e.g., younger children w/ parental consent) • •Detailed, comprehensive document • •Voluntary agreement of an individual, or his/her authorized representative who has legal capacity to give consent, exercises free power of choice, without undue inducement or any other form of constraint or coercion to participate Informed consent - for a certain age of children such as 9 needs the child's assent or approval

when is an RCT most appropriate

•When there is sufficient uncertainty about the utility of an intervention (i.e., equipoise) • •The question to be answered by RCT should be SAFE from participant perspective •i.e., no undue risk/harm • •When the research question is ethically appropriate to be answered by an RCT •What is considered ethical may change with time and accumulation of knowledge - RCT and knowledge of harm so wouldn't give pregnant moms alcohol

sponsor-investigator guidelines

•When using an investigational new drug that is subject to a manufacturer's IND application, Sponsor-Investigators may refer to the manufacturer's IND or marketing application for technical information. When using an investigational new drug not subject to a manufacturer's IND application, Sponsor-Investigators submit all technical information to support the IND

data safety monitoring

•Who will be involved in monitoring, how often •Data monitoring committee process

product development (clinical investigations) INDs

•are submitted by a corporate entity or a physician who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed.

RCTs continue to be

•be the "gold standard" for clinical trial design

information asymmetry

•consumer is uninformed about the true value of a good Patients don't know and can always observe the impact of the drug on their health- think about anti-hypertensive or asthma drugs

treatment IND

•is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place. •treatment IND is for people that are about to die such as phase 4 cancer; compassionate use when nothing is left to treat them

clinical treatment (expanded access) INDs

•refer to the use of an investigational new drug outside of a clinical trial by patients, with serious or life-threatening conditions and no comparable or satisfactory alternative therapy exists, who do not meet the enrollment criteria for the clinical trial in progress. -It applies to use of investigational new drugs when the primary purpose is to diagnose, monitor, or treat patient's disease or condition.

investigator IND

•submitted by a physician who both initiates and conducts the investigation, and under whose immediate direction the investigational drug is administered or dispensed.

investigator's brochure

•understand what are credentials or justification that scientist have knowledge to do this

general investigational plane

•what is study, how you randomizing patients, how many patients get active ingredient or placebo

abbreviated new drug application (ANDA)

○Process where generic products are approved following the expiration of a patent held by an innovator company. ○Requires proof that the generic's pharmacokinetics, bioavailability, and clinical activity are similar to the innovator product.

supplemental new drug application (SNDA)

○Submitted after NDA approval ○Covers changes in synthesis, production procedures, manufacturing locations, packaging, labeling, indications

drug

◦Articles recognized in the official USP/NF or Homeopathic Pharmacopoeia, or any supplement to any of them; and ◦Articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and ◦Articles other than food intended to affect the structure or function of the body or man or other animals; and ◦Articles intended for use as a component of any article specified in clause A, B, or C ◦No distinction between prescription/non-prescription ◦No distinction between articles for use in animals or humans