Need a New Drug? Exam 2 Study Guide
What is an OTC monograph? How is the monograph developed?
System that is the regulatory pathway for bringing an OTC drug product to market without individual FDA evaluation. Has all clinical info for particular drug, standards for manufacturing, standards for dose amounts, and standards for dosage forms (GRASE- generally recognized as safe and effective)
In 1962, Congress directed the FDA to assure the efficacy (effectiveness) of each drug product approved in the US. This new responsibility was associated with the lack of demonstrated efficacy and toxicity of which drug product?
Thalidomide; was at the time under FDA review but not yet marketed in US. In Europe, reports of birth defects in children born to women using this product. Pure luck that drug wasn't available in US because none of the test available at that time would've identified mechanism responsible for defects. -Drug Amendments Act of 1962-
Which dose (relative to the doses tested in Phase I) are typically tested in Phase II human clinical trials?
The drug is studied in patients with the target disease to determine its efficacy and the doses to be used in any follow-on trials
What was the "Nuremburg Code" and what did it accomplish?
The first internationally recognized code of medical research ethics. Clarifying the standards of integrity that constrained the pursuit of knowledge. Guide not a law.
What is the background of the principal investigators typically involved in Phase III human clinical trials?
The investigators are usually specialists in the disease being treated
Phase II clinical trials (when conducted in volunteers with disease of interest) are often "double-blind". What are the characteristics of a double blind study?
The patient AND investigator don't know if the patient is receiving the investigational drug, some other standard treatment, or placebo. Limits any interpretation or reporting bias based on patient or investigator input.
What are 3 confounding factors known to contribute to variability in human clinical trials?
The variable natural history of most diseases The presence of other diseases and risk factors Subject and observer bias and other factors
Describe how "Fast-track", "priority approval" and "accelerated approval", and the identification of "breakthrough" products contribute the accessibility of important new drug products before full clinical evaluation and FDA review has been completed.
They are FDA programs that have been in place to speed entry of new drugs into the marketplace
What are the characteristics of an OTC drug that assure its safety when used by the consumer?
They have little potential for abuse or misuse and adequate labeling to self-diagnose/select/treat/manage their condition
Are the volunteers in Phase II trials healthy or do they have the disease of interest?
They have the disease
How many volunteers are typically included in Phase III clinical trials?
Thousands
Why were independent committees of researchers originally formed to review research involving humans?
To protect the subjects being tested on and because they were afraid that some negative side effects from testing was going undetected.
How is the Office of Global Regulatory Operations and Policy different than most of the other FDA Offices or Centers
Tries to work with other regulatory agencies across the world to assure free trade, safe importation, and safe exportation of food and drug products.
Describe how ICH membership expedites global drug product importation.
US and Switzerland
Who approved and participated in these studies?
University of Chicago received a grant approved by lawyers and the court to do this study.
Can a drug product be covered by more than 1 patent?
YES
What also must the FDA approve?
all promotional and marketing materials provided by a drug product sponsor. This includes direct-to-consumer information (television commercials, internet or print advertisements) and information provided to prescribers.
Describe Investigator IND
does not have to be a major pharmaceutical company; can be drug company or physician; (new drug compound not yet studied; drug compound already approved, now seeking other uses)
Describe dosage for generic vs. branded medication
generic drugs are only available at the identical dose strength in the identical dosage form as the branded medication
How is the process of clinical trial evaluation different between Koseisho and the trial sponsor compared to the FDA and the trial sponsor?
how clinical trials are conducted and the results are evaluated Japanese: continuous stream of feedback
Where are Phase I human clinical trials typically conducted? What is the background of the principal investigators?
major cancer centers
What is the Center for Biologics Evaluation and Research (CBER) responsible for?
most of the vaccines, blood, cell, and tissue-based medical products available in the US.
Describe Treatment IND
not available to patient population in the US but has established safety and efficacy record; may still be under review in the US, may be approved in another country and US patients might benefit from it, may be a currently marketed drug product in US being used to treat a disease different from which it was originally approved
What role does the Office of Global Regulatory Operations and Policy play at the FDA?
primarily administrative role but also has a huge impact on drug development process (because responsible for safety of pharmaceuticals around world)
When was the FDA first formed and given the responsibility to regulate the interstate trade of medicinals?
(Food and Drugs Act of) 1906
Describe Emergency Use IND
(potentially life saving drug may be available; emergency situation, not enough time for IND submission; patients do not meet current study criteria; FDA contacted about use of drug in specific individual patient)
LECTURE: Clinical Investigation
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LECTURE: Drug Development and Approval in Asia
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LECTURE: Drug Development and Approval in Central and South America
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LECTURE: Drug Development and Approval in Europe and Canada
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LECTURE: Drug Regulation
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LECTURE: FDA
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LECTURE: Generic Drug Development
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LECTURE: Introduction to Generics
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LECTURE: Over-the-Counter Drugs
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READING: Basic & Clinical Pharmacology. Chapter 1: Introduction: The Nature of Drugs & Drug Development II. Drug Development & Regulation. Evaluation in Humans (and Fig 1-6)
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READING: ClinicalTrials.gov Background
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VIDEO: "Protecting Human Subjects"
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WEBSITE: ClinicalTrials.gov (Instructions for Patients and Families)
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Week 4:
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Week 5
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Week 6
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Describe the pricing review process utilized in Canada. Note that pricing discussions take place during the review process and are finalized immediately prior to the final drug approval. Why do these pricing discussions take place?
-patented medicines prices review board -max average potential price established Negotiated prior to approval Process used so the health system is assured they are getting the best healthcare return for the government's investment
What are the goals of the mandatory clinical trials conducted in Mexican/Hispanic populations for approval to market in Mexico?
...Mexicans had to be used in experiment too
What is the typical drug review (NDA equivalent) time in India?
1 year
What are 2 common reasons for drugs to fail in Phase I clinical trials?
1. Unexpected toxicity 2. Ineffectiveness in humans *For every 5 drugs only 1 makes it to approval stage
Identify the 6 required components of a clinical study protocol.
1.Reason for conducting the study 2.Who may participate in the study (eligibility criteria) 3.Number of participants needed 4.Schedule of test, procedures, or drugs and their dosages 5.Length of study 6.What information will be gathered about the participants
How many volunteers are typically involved in Phase 0 trials?
10-25
What is the minimum number of years of patent protection for new drugs resulting from the Patient Protection and Affordable Care Act?
12 years of patent protection for new drugs
What does a "bioequivalence" test demonstrate to the FDA?
2 drug products provide the same biological effect in user
How many volunteers are typically included in Phase I clinical trials?
20-100
In order for a disease to be classified as an "Orphan Disease", how many individuals in the US can be affected?
200,000
What is the maximum number of days the EMA can take to review an "NDA" for marketing approval? When delay time is incorporated for additional information requests, what is the average time for drug product approval by the EMA?
210 days max; 358 days ~ 1 year
What is the typical review time period needed for marketing approval in Canada?
355 days
What is the typical review time (NDA equivalent) for drug approval in Japan?
6 mo- 2yrs
How many volunteers are typically included in Phase II clinical trials?
A few hundred
The regulatory application that is submitted for the approval of a generic drug is referred to as:
Abbreviated New Drug Application (ANDA)
Describe the accessibility differences between "prescription" medications and "over the counter" medications.
Access to prescription medications are limited and require authorization by a practitioner OTC medications are considered safe for use by the public without a prescriber's authorization
For OTCs, which types of products must have tamper-resistant packaging and which products are exempt from these packaging requirements? Why is tamper resistant packaging required?
All OTC products (except for dermatological, dentifrices, insulin, and lozenges) MUST have tamper-evident packaging. Helps user monitor the quality of the product post-manufacturing.
What are the characteristics of the volunteers in Phase III trials?
All have the disease of interest
Describe the types of human clinical trials conducted by a generic drug company for an ANDA submission. What is the goal of these studies? How many volunteers are typically included in these studies?
Bioequivalence trial: Must demonstrate that their generic product acts the same way as the innovator product. Small number of volunteers (100 or less)
What is the difference in naming between an "innovator/brand" drug and a generic drug?
Brand named drugs: only supplied by one drug company and sold under a trademarked name Generic drugs: may be supplied by multiple companies and sold under the name of the active ingredient
Which South American country has the most developed drug regulatory and drug manufacturing sector?
Brazil
What types of information are included in "FDA Guidances"?
CFR-Code of Federal Regulations (Chapter 21): when FDA uses federal law to support its practices; FDA takes the laws passed by Congress and determines how they will be implemented and the FDA adds additional detail regarding implementation plans to elaborate how they expect laws to be upheld by drug manufacturers or food suppliers.
Which section of an IND is also required for an ANDA
CMC
What additional contents beyond those initially described in the IND are included in an NDA?
CMC, nonclinical (pharmacology and toxicology), clinical (establish safety and efficacy), labeling, patents
What is the name of the drug regulatory agency in Mexico?
COFEPRIS (Comisión Federal para la Protección contra Riesgos Sanitarios)
How are clinical trials typically funded?
Can be sponsored or funded by pharmaceutical companies, academic medical centers, voluntary groups, and other organizations, in addition to Federal agencies such as the National Institutes of Health, the U.S. Department of Defense, and the U.S. Department of Veterans Affairs. Doctors, other health care providers, and other individuals can also sponsor clinical research.
What effects do generic drugs have on drug process.
Causes drug cost to go down and encourages research by the innovator of drug companies because net profit decreases as well. Help keep insurance premiums down and helps consumers save billions of dollars per year.
What is the name of the drug regulatory agency in India?
Central drugs standard control organization (CDSCO)
What is the name of the drug regulatory agency in China?
Chinese FDA
In order to shorten the time needed to develop new drugs, describe which types of toxicology trials can be conducted concurrently with ongoing human clinical trials.
Chronic safety testing in animals, including carcinogenicity studies
What 2 types of research does this term include?
Clinical trials (interventional studies) Observational studies
What is a unique requirement regarding the clinical trial populations when seeking drug approval in Japan?
Clinical trials must be conducted in a population of Japanese volunteers
Briefly describe the major principles outlined in the Nuremburg Code.
Code was a guide, not a law. 10 principles 1.Voluntary consent is essential 2.Experiment should not be unnecessary 3.Experiments should be based on animal experimentation 4.Experiments should avoid unnecessary suffering 5.Only scientifically qualified persons should conduct experiments 6.Subjects should be permitted to withdraw at any time 7.experimenters should be prepared to stop experiment at anytime if a subject is in danger
What is an IRB - Institutional Review Board?
Committee of scientists and nonscientists at the local level that review research protocols and consent forms to ensure that the rights and welfare of research subjects are protected.
Describe how the incidents associated with the Wichita layers and their studies of jury behaviors were also impacted by the Nuremburg code and human research ethics, even if their activities did not involve research in the biomedical sciences.
Congress concluded that juries were not to be recorded because if they were told they were being recorded it could change their actions and if they were not told then it would violate the principal in the Nuremberg Code that people should have informed consent.
What are the primary goals/outcomes of Phase III clinical trials?
Continue to demonstrate that the drug product is effective in intended disease state; safety and side effects still evaluated
What components must be present in an OTC label? Are OTC labels reviewed by the FDA in the same way as for NDAs?
Description of active ingredients and their purpose, inactive ingredients, product's uses, warnings, direction, other information.
How are generic drugs able to enter the marketplace at a lower price than the brand name drug?
Discovery, pre-clinical studies, and clinical studies are all very expensive to conduct and generic drugs don't have to do this studies again; generic companies don't advertise directly to consumers and don't bear advertising costs.
What are the concerns regarding differing regulatory standards in India for domestically-produced and marketed drug products versus those produced for export?
Domestic vs. international production standards
What are the typical doses used in Phase 0 trials?
Doses lower than the anticipated therapeutic dose
What are the concerns regarding differing regulatory standards in China for domestically-produced and marketed drug products versus those produced for export?
Drug product access within china and drug product export outside of china
What types of drug products are most likely to be designated for "fast-track" review?
Drugs that utilize a new or unique mechanism of action, orphan drugs, and even generic drugs
What are the primary goals/outcomes of Phase II clinical trials?
EFFECTIVENESS; (Still investigating safety and side effect profiles)
Describe the decentralized approval process that allows each country within the European Union to continue to approve drug products specifically for marketing in an individual country.
Each member state retains ability to approve for marketing in only that member state. Request for marketing of a product in more than one member state simultaneously when the drug does not fall within the essential drugs list for centralized procedure review (~200 days)
National Research Act
Establishment of review boards to review human research. 1974
What is the EMA (including its full name)? When was it established?
European Medicines Agency; est. 1995
What are the primary goals/outcomes of Phase I trials?
Evaluate drug safety; DOSE RANGING
What are the goals/milestones of the Phase 0 trials? (What do the sponsors want to know about the drug?)
Evaluate potential differences in results from animals and cell culture models and to confirm or reject preclinical results before testing in larger populations
The variable natural history of most diseases
Evaluating a large enough population of subjects over a sufficient period of time Crossover design: alternating periods of administration of test drug, placebo prep, and the standard treatment (if any) in each subject.
Who typically conducts clinical studies (principal investigator and scientific team).
Every study is led by a principal investigator (often a medical doctor) and have a research team (doctors, nurses, social workers, and other healthcare professionals)
Phase I trials are typically "open label". What does this term mean?
Everyone knows the patient is receiving the test drug and what dose they will be receiving- for appropriate monitoring
Why is it unethical to conduct human clinical trials to demonstrate the effectiveness of a generic drug product?
Exposing people to clinical trials when you already know the result is unethical
What is the Center for Drug Evaluation and Research (CDER)?
FDA unit with the greatest responsibility in the evaluation and regulation of drug products (including generic drugs) available in the US
In December, 1946 a group of German scientists was on trial in Nuremburg for the unethical use of humans in experiments conducted during World War II. These trials stimulated what activities?
First modern effort to formulate an international code of ethics protecting human research subjects
The significant users fees (PDUFA and GDUFA) for filing drug approval documents with the FDA are used by the FDA to accomplish what goals?
Fund drug approval process, hire additional FDA reviewers so the time for NDA review can be shortened; time to develop generic drug and review approval application can be shortened
The product development and validation investigations conducted by a generic drug manufacturer are equivalent to what steps at what stage in the development of a brand name drug product?
GMP (good manufacturing practices) steps- like preclinical IND filings
Compare and contrast the similarities and differences between generic and brand product review as depicted on slides "Summary of Generic Review" and "Innovator vs Generic".
Generic Review- must have same active ingredients, same labeled strength, same dosage form and same administration, show it is 'bioequivalent' to brand name, CMC, maintain stability as labeled before it, comply with federal regulations for current good manufacturing practices and give description of facilities used for manufacturing, processing, testing, labeling, and controlling, inspection at manufacturing site Innovator vs. Generic- NDA and ANDA have same CMC, show its 'bioequivalence' to innovator, don't have to conduct clinical trials, must demonstrate it acts same way as innovator product
Does a generic drug need to have the identical stability/shelf life as the brand name product?
Generic drug needs to maintain identical stability but does not need to have same shelf life as the brand name product
Describe the issues associated with India's state-controlled regulatory bodies in addition to the national regulatory agency.
Governmental structure is not as nationalized as it is in other countries; internal state has had much more power than the national agency. They have operated previously under their own rules.
What are the characteristics of the volunteers who typically participate in Phase I trials?
Healthy volunteers except in circumstances like cancer treatments because it would be wrong to expose healthy people to those drug compounds
What types of volunteers are usually used in bioequivalence studies?
Healthy volunteers rather than individuals in disease state.
What role does the Jurisdictional Formulary /Regional Review process play in the approval of drug products in Canada? Which type of drug product most frequently uses this process?
Helps reduce workload for national health bureau-determine what part of Canada it'll be available ; new generics or other drugs with long history of use that need reimbursement
What were the issues at the core of this case?
How could researchers justify recording jurors without their knowledge, researchers argued that they had to do it without their knowledge or else their behaviors could change.
What types of materials can be included to provide "informed consent"?
In addition to informed consent document: recruitment materials, verbal instructions, Q&A sessions, and activities to measure participant understanding
What dose is administered during Phase I trials (relative to estimated therapeutic dose)?
Increasing amount to determine what the safe range is; try to determine the highest dose without significant toxicity; can be single dose or multiple dose exposures
What are the 3 types of INDs accepted by the FDA and describe the typical sponsor of each
Investigator, Emergency Use, Treatment
What is an "observational study" in the context of human clinical research? Can interventions be involved in these studies?
Investigators assess health outcomes in groups of participants according to a research plan or protocol; participants may receive interventions or procedures as a part of their routine medical care, but participants are not assigned to specific interventions (like in clinical trial)
What changes were made regarding informed consent as the result of the negative effects of thalidomide, an investigational drug in the US in the early 1960's?
It resulted in physicians being required to inform people if a drug was in its experimental stage and requiring them to get consent from the patients that were testing it.
The presence of other diseases and risk factors
Known and unknown diseases and risk factors can influence the results of a clinical study
What is the name of the drug regulatory agency in Japan?
Koseisho
Why is the IND review time in China longer than in the US?
Lack of sufficient review personnel and IND backlog
Which type of drug-induced effects are most likely to be first identified in Phase IV testing?
Low-incidence drug effects
How is bioequivalence demonstrated (experimentally measured) to demonstrate equivalence to the FDA.
Measuring the drug concentration in the blood
Briefly describe the goals of Phase IV human clinical testing. When does Phase IV commence?
Monitoring safety of the new drug under actual conditions of use in large number of patients
What quality standards do generic drug products need to meet?
Must meet the same FDA standards for quality as brand name drug products
What is the name of the drug regulatory approval agency in Canada?
NDS (New Drug Submission); close to NDA
What does the abbreviation "NDA" represent?
New Drug Application- document contains all info on IND + additional work conducted during trials
In 1938, Congress added the assurance of drug product safety to the FDA's responsibilities. This action was in response to which situation involving a toxic medication?
New antibiotic: Sulfanilamide that accidentally got matched with a toxic solvent in a product sold in US and caused a significant number of deaths -Federal Food, Drug and Cosmetic Act of 1938-
What 3 major categories of information are required in an IND for review by the FDA?
Nonclinical; animal pharmacology and toxicology, pharmacokinetic and pharmacodynamic data, foreign clinical data, safety-focused CMC-Chemistry, Manufacturing, Controls; manufacturing data, composition and stability data, quality control process Other; clinical plan, investigator's, brochure
What information about a human clinical study is included on ClinicalTrials.gov?
Number of participants enrolled, condition, intervention, what phase it is in
Compare and contrast the NDA approval process and the OTC monograph process with regard to review and approval of drug products.
OTC; no pre-market approval and no FDA-mandated review (pre or post-market) NDA; pre-market approval and FDA review
How are Phase IV clinical trials different from Phase I-III trials?
Occur post approval to confirm safety in large/global population
When can a generic drug manufacturer bring a generic drug product into the commercial marketplace to compete against a brand name drug?
Once a patent expires
What is the typical review time (NDA equivalent) for drug approval in China?
Over 6 months
What is the congressionally mandated role of the US FDA?
Oversee the safety and effectiveness of food and drugs available in the US
How is a "clinical trial" defined?
Participants receive specific interventions according to the research plan or protocol created by the investigators; interventions may be medical products (drugs or devices), procedures, or changes to participants' behavior (diet)
Describe the Tuskegee Study and identify the breaches in "ethical conduct" based on the current (2017) definitions of human subjects research.
Participants with syphilis were tracked to see the natural path people went down if they had syphilis and it was not treated. This was unethical because patients were tracked but not treated even after penicillin was invented and known to be a cure for syphilis. Started in 1932 and continued for 40 years
Subject and observer bias and other factors
Patients tend to respond in a positive way to any therapeutic intervention by interested, caring, and enthusiastic medical personnel Placebo response Single-blind design: placebo for patient Double-blind design: placebo for patient AND investigator
Which phase of human clinical testing has the highest drug failure rate?
Phase 2 (only 25% of innovative drugs move on to phase 3)
If a non-China-based sponsor wants to conduct clinical trials in China, at what investigational stage must the product be in other countries?
Phase II
What is unique about a Phase IIIb clinical trial?
Post NDA filing
Are Phase 0 trials conducted before or after the approval of the IND?
Pre-IND
Describe the "safety" differences between prescription drug products and OTCs.
Prescription medications are determined to have "risk" and need to be supervised by a practitioner OTC medications are considered safe for use by the public
Why is Puerto Rico the largest exporter of pharmaceutical products in the Central/Southern American region?
Puerto Rico's status as a territory of the US. (Tax incentives to produce products in Puerto Rico)
The reviewer panels (not advisory panels) for Health Canada have a different composition/membership compared to FDA review groups. What is the most significant difference?
Rather than a full staff of governmental employees reviewing application, they use a combo of health Canada employees and other non governmental experts
identify the major product categories of materials the FDA has responsibility to oversee to assure their safe use by citizens of the US
Regulation and supervision of food safety, tobacco products, dietary supplements, prescription and over-the-counter pharmaceutical drugs (medications), vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices, cosmetics, animal foods & feed, and veterinary products
Where are Phase III trials typically performed?
Settings similar to those anticipated for the ultimate use of the drug
Where are Phase II trials typically performed?
Special clinical centers like university hospitals
Define the term "Clinical Study"
Study that Involves research using human volunteers (participants) that is intended to add to medical knowledge.
In order to shorten the time needed to develop new drugs, describe which types of toxicology trials need to be completed before an IND is filed
Sufficient acute and subacute animal toxicity studies
What is the "Belmont Report" and how are its content currently used and applied?
Summarizes the basic ethical principles that should accompany research, and used to make sure research is ethical and makes sure subjects are protected.
