Applications of Pharmacy Law and Ethics: Modules 1 - 3

Module 1.1: Ethics of Clinical Research

Module 1.1: Ethics of Clinical Research

Research

A systematic investigation designed to develop or contribute to generalizable knowledge.

Human subject

A living individual about whom an investigator (including student researchers) conducting research obtains

• (1) Data through intervention (ex., blood draw) or interaction (ex,. interview) with the individual, or

(2) Identifiable private information (ex. medical record)

Intervention includes:

– Physical procedures by which data are gathered (for example, venipuncture or BP reaadings) and

– Manipulations of the subject or the subject's environment that are performed for research purposes (don't need to directly intervene)

– Interaction includes communication or interpersonal contact between the investigator and the subject.

Private information

Includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place./

Clinical Research vs. Clinical Practice

Clinical Research

• Goal: Produce generalizable knowledge to benefit future patients

• Research Protocol:

→ Restrict variation to specified parameters to reduce variables that might confound results (strict)

→ Terminology: Investigator, subject or participant, research intervention, research protocol

Clinical Practice

• Goal: Provide the best care for the individual patient

• Treatment:

→ Increase or reduce the dosage of a drug (flexible)

→ Add, subtract, or substitute drugs to optimize effectiveness and reduce AEs

→ Terminology: Practitioner, patient, treatment, standard care

Limits of evidence-based medicine and drawing inferences for specific patients

• Research reduces the number of confounding variables (reduces generalizability)

• Research subjects are selected by using:

– Exclusion criteria

– Inclusion criteria

• BUT Patients come without exclusion or inclusion criteria

– They have multiple conditions and confounding variables

– You will always be using data derived from persons restricted by study criteria and applying that data (through inferences) to an individual patient in front of you who may not meet those criteria

Clinical research uses methods that are unacceptable in clinical practice

Practice

• Choice of intervention based on the best interests of the patient and patient choice

• No placebo (would be unethical)

• Physician and patient know what intervention was selected

Research

• Random assignment to intervention or control arms

• Subject may receive a placebo

• Blinding of investigator and subject (double blinded)

• Would be unethical if it did not contribute to a higher level of evidence used to establish the standard of care and there was informed consent taken

Why might a patient (and provider) be confused about the distinction between clinical research and pratice?

• The lines can become blurred...

• Clinical research is typically done in the context of clinical practice:

– therefore,

• easy for the patient to be confused about whether she is a patient or a research subject at any given time &

• hard for a health practitioner to restrict instinctive desire for the patient's best interest in order to produce valid results

• Patient/subject can also have both roles, receiving both the SOC and an investigational drug, which is common for cancer patients

When is it acceptable to implement a research protocol despite the ethical concerns of not following the patient's best interest?

– There is uncertainty ("equipoise") about what the best intervention is to justify subjecting human subjects to the risks of randomization or placebo

– And the patient grants informed consent to being a research subject (rather than a patient).

Clinical Equipose

• When the relevant community of clinicians is sufficiently uncertain about which of two or more interventions is best...

• ...and a randomized clinical trial will resolve the ambivalence of the field as to which is best.

• Or when two groups each prefer one intervention, but neither has sufficiently convincing evidence that theirs is better than the other.

• Makes it ethical to have randomization or randomization with a placebo

Patient equipoise

• Even if clinicians are in equipoise (uncertain as to which intervention is best)

• Patients may have a preference and therefore not be willing to be randomized, making it impossible to do a RCT

• Example: randomization between radical prostatectomy, x-ray radiation, proton beam radiation, etc.

Hierarchy of Research Designs

Systematic Reviews and Meta-Analysis > Double Blind RCTs > Cohort Studies > Case-Control Studies > Case Series > Care Reports > Ideas, Editorials, Opinions > Animal Research > In vitro ("test tube") research

When is a placebo ok to use?

When the condition/disease will cause little or no harm

Ex. Minoxidil (baldness treatment)

Clinically Meaningful Endpoints

Used in phase 3 where effectiveness is looked at

• Improved survival

• A benefit detectable to the patient (improved symptoms, functional capacity)

• Reduced chance of condition or disease complication (apparent to the patient)

Surrogate endpoints

• A laboratory measure or a physical sign that is intended to be used as a substitute for a clinically meaningful endpoint

- Ex. Blood pressure, LDL levels

• Used mainly in phase 1 when safety is the primary concern

• Easier and cheaper to measure

• Need to be validated to justify their use.

- Relationship, such as blood pressure, must be shown to have a direct bearing on clinically meaningful endpoint, such as heart failure or stroke, in order to obtain clinically useful knowledge.

Compassionate Use Exemption

• Allows the patient to use an investigational drug despite not being apart of the clinical trials

For the FDA to grant the exemption, a patient must meet certain criteria:

• The disease is serious or life-threatening.

• The patient has exhausted all available treatment.

• Patient not eligible for clinical trials of the drug.

• Patient's physician agrees that the patient has no other options

• Patient's physician feels the benefit justifies the potential risks of the treatment.

• The company that makes the drug agrees to provide it to the patient (MOST DIFFICULT PART)

"Right to Try" vs "Compassionate Use Exemption"

• Right to Try laws bypass the FDA approval to use an investigational drug, whereas FDA approval is needed (and usually granted) for the "Compassionate Use Exemption"

Right to try Law

• Patients don't have to go through the FDA anymore for investigational drugs; they can go through the manufacturer

• Federal law passed in 2018, although it was unnecessary since the FDA approves 99.4% of compassionate use requests (but it saves time! So I wouldn't call it unnecessary)

Problems with right-to-try laws (and with compassionate use exemption)

• Often gives patients false hope/therapeutic misconception (need to provide realistic expectation to patient since it is a unproven treatment)

• Since offered outside a clinical trial, cannot provide reliably useful data

• Rx drug manufacturers not required to give the drug

• If too many exemptions, availability of trial will prevent or slow down sufficient data collection to obtain approval

• Insurance won't cover these uses ($$$)

• For new federal right to try law, allows access after Phase I, which only tests safety, not efficacy, so no indication whether benefits will balance risks

After what Phase does the federal right-to-try law allow access to investigational drugs?

Phase 1

Informed Consent

• Explanation of purpose

• Duration of participation

• Description of procedures and identification of any that are experimental

• Reasonably foreseeable risks or discomforts

• Benefits to the subject reasonably expected

• Appropriate alternative courses of treatment, if any that may be advantageous to the subject (instead of the trial)

• Statement of confidentiality of records identifying the subject

If greater than minimal risk...

• Explanation of any compensation to be paid or

• Explanation of any medical care to be provided if injury occurs

• Whom to contact in case of

– Questions about the research

– Questions about the subject’s rights

– Occurrence of injury

• Participation is voluntary; volunteers may quit at any time.

• Refusal to participate will involve no penalty

– No loss of benefits

– Subject may discontinue participation at any time without penalty or loss of benefits

Clinical Research Phases

Stages of testing drugs on human subjects.

Lecture 1.2: Drug Advertising by Manufacturers and Pharmacies

Lecture 1.2: Drug Advertising by Manufacturers and Pharmacies

The _________ regulates prescription drug advertising whille the ________ regulates over-the-counter drugs.

FDA; FTC

Why can't the government ban the advertising of drugs?

Due to the First Amendment (murica), but commercial speech, like advertising, can be regulated more than political speech or artistic expression

Any regulation of commercial speech will be evaluated on four factors established by the U.S. Supreme Court:

1. Ad cannot be misleading or related to unlawful activity

2. Gov’t interest in the regulation must be substantial (not trivial)

- Ex. Public safety of people taking Rx Drugs

3. Regulation must directly advance the gov’t. interest

4. Restriction of speech must be the minimum restriction necessary to serve gov’t. interest

- Cannot be broad, must be tailored to a specific problem

Prescription Drug Advertising: Manufacturer to Professionals

• Section 502(n) requires all advertisements to contain a “true statement”

– including the established

(1) name of the drug and the

(2) formula with

(3) quantitative list of ingredients

– and a “brief summary” of

(1) side effects

(2) contraindications, and

(3) effectiveness.

• True statement is not met if

– advertising is false or misleading,

– does not present a fair balance (accurate view of risks vs benefits), and

– fails to reveal material facts (what a professional will find important before prescribing)

• Reminder advertising is exempt.

What two components does a "manufacturer to professionals" need to contain?

A “true statement”

– including the established

(1) name of the drug and the

(2) formula with

(3) quantitative list of ingredients

A “brief summary” of

(1) side effects

(2) contraindications/warnings, and

(3) effectiveness.

What kind of advertising is exempt from true statement regulation?

Reminder

Reminder Ads Exempt

• Focus on the name with no information on uses

• Can include name, ingredients, dosage form, package quantity, price

• No suggestion of use, including graphics/logos

• May NOT be used for black box products

– Except for price information

Fair Balance

The law requires that product claim ads give a "fair balance" of information about drug risks as compared with information about drug benefits. This means that the content and presentation of a drug's most important risks must be reasonably similar to the content and presentation of its benefits.

Advertising distinguished from labeling

• Advertising

– Promotional messages in traditional media: print media (journals, magazines, newspapers), radio, television, and telephone

• Labeling

– brochures, booklets, mailings, bulletins, calendars, and other information distributed to healthcare professionals by a manufacturer.

• Advertising is only required to include a “brief summary” of risks, while labeling must contain the entire package insert.

__________ is only required to include a “brief summary” of risks, while __________ must contain the entire package insert.

Advertising; labeling

Advertising: Brief Summary vs. Major Risks Disclosure

(See Chart)

Common Promotional Issues

• Omitting or minimizing of risk

• Overstating the drug’s benefits (broadening of indication) compared to what the labeling says

• Failing to present a “fair balance” of risk and benefit information

• Omitting material facts about the drug (what a prescriber should know before prescribing)

• Making claims that are not appropriately supported (substantiated)

• Misrepresenting data from studies

- Distorting the studies, only presenting part of what the study included

• Making misleading drug comparisons (Unsubstantiated superiority/comparative claims)

Manufacturer must make "_____________________" for the dissemination of the labeling,

adequate provision

"Adequate Provision" includes:

• Provision for the consumer to get

– full labeling information

– in language comprehensible to the public,

– by a multi-faceted approach from four sources:

(need at least one of them)

▪ toll-free phone number

▪ internet web-page address

▪ referral to concurrent print ad or brochures in convenient outlets

"See your pharmacist for a brochure."

▪ referral to a healthcare practitioner

" Talk to your doctor about this"

What are the four sources that can be used for the "adequate provision" clause?

1. Toll-free phone number

2. Internet web-page address

3. Referral to concurrent print ad or brochures in convenient outlets

"See your pharmacist for a brochure."

4. Referral to a healthcare practitioner

" Talk to your doctor about this"

Industry-supported educational programs

– History of manufacturers disguising biased promotional activities as objective professional education

– Companies also used fishing, skiing, and other vacation activities to reward high prescribers of their Rx drugs.

– Companies selected speakers based on who favored their drugs

– Paid the speakers hundreds of thousands of dollars per year to give continuing ed. talks.

– Off-label uses are heavily promoted without sufficient evidence of effectiveness

When does the FDA regulate an industry-sponsored program?

Programs that are not independent and promotional are subject to labeling and advertising restrictions, such as “true statement” and “fair balance.”

– In these types of program,s off-label uses would be scrutinized

Physician Payment Sunshine Act

Mandates disclosure by drug and device manufacturers to DHHS (Department of Health and Human Services) of non-trivial payments to physicians and teaching hospitals

FDA Bad Ad Program

FDA enlists health professionals to report misleading promotional activities.

Prescription Drug Advertising: Manufacturer to Consumer (Direct-To-Consumer Advertising)

• Significant congressional and public controversy

• No specific laws and regulations, thus §502(n) applies

• Because compliance with §502(n) is impractical, FDA allows manufacturers to apply the “adequate provision” requirement.

• Consumer must be offered full labeling information from one or all of the four sources.

• For DTC print advertising, FDA encourages manufacturers to present key risk information in user-friendly ways.

• Reminder and help-seeking ads are exempt from requirements.

• GAO (Government Accountability Office) reports noted FDA weaknesses in regulating DTC ads.

• FDAAA (FDA Amendments Act) has provided FDA with the authority to require 15-day pre-review of ads

Promoting Prescription Drugs and Devices Through Social Media

• FDA guidance documents relating to standards for

– Communications through interactive promotional media

– Communications through social media platforms with space limitations

– Correcting third-party misinformation through the Internet or social media

Promoting Prescription Drugs for Off-Label Uses

• Manufacturers providing off-label use information is very controversial

• FDAMA (FDA Modernization Act) allowed the practice with restrictions but expired in 2009

• 2009 compliance guide reinstituted most of FDAMA off-label use provisions, clarified by 2014 compliance guide.

• U.S. v. Caronia decision may limit FDA’s authority to regulate off-label use communications.

• Manufacturer can respond to off-label use information requests from physicians

Nonprescription Drug Advertising by Manufacturers

• FTC under FTC Act regulates deceptive ads.

• Ads are deceptive when they are likely to mislead reasonable consumers

• Ad claims must have a reasonable basis.

• FTC only needs to prove consumers are “likely” ( >50%) to be misled, not that they actually are misled.

• FTC has the authority to require corrective advertising

Lanham Trademark Act

• Prohibits use of any false description or representation

• Allows for private cause of action and recovery of monetary damages

• A competitor can sue if they feel that their product was misrepresented without adequate evidence

Drug Advertising by Pharmacies: Price advertising

– Considered reminder advertising and thus exempt from § 502(n) ("true statement") provided that certain conditions are met

• ad must only include info on price, NOT info on safety, efficacy, or indications for use.

• ad contains the proprietary name, the generic name, drug strength and dosage form and price for specific quantity of the drug.

• ad may contain other information such as professional services, if not misleading

• price stated in the ad must include all charges to the consumer, although mailing or delivery fees may be listed separately.

Pharmacy ads for OTC products

• Regulated by Federal Trade Commission (FTC)

• Strict liability for violations, regardless of the pharmacy’s knowledge or intent.

– FTC brought action against the manufacturer of X-11 tablets and against Pay ’n Save Drug chain, even though Pay ‘n Save did not create nor have knowledge of the accuracy of the ads, but only accepted and disseminated the ads from the manufacturer.

– FTC brought action against Rite-Aid for deceptive ads that its product “Germ Defense” prevented, or reduced the severity of colds and flu, as well as against the maker of a similar product, “Airborne,” with similar claims.

– Class action suit won by consumers against Walgreen’s for its generic version of Airborne

Constitutionality of State Pharmacy Advertising Laws

• Prior to the 1976 Case of Virginia Board of Pharmacy vs. Virginia Consumer Council, state laws prevented pharmacists from advertising price.

• Virginia decision established that the First Amendment applies to commercial speech and to recipients of the speech.

• Virginia decision does not bar states from (can advertise drug prices, but need to follow the things listed belows)

– prohibiting false or misleading advertising,

– advertising professional superiority, or

– from making it illegal for pharmacies to offer discounts or rebates, and

• Many states do have such prohibitions

• Pharmacies can advertise prices, but cannot do any of the things listed above.

Module 1 Readings

Module 1 Readings

What info is needed in a NDA?

1. Full reports of investigations showing the drug's safety and efficacy, needs to be "substantial evidence"

2. The drug's components and composition

3. The methods, facilities and controls used in manufacturing, processing and packaging the drug

4. Samples of the drug and its components

5. The proposed labeling of the drug

Substantial evidence

Defined as the findings of adequate and well-controlled investigations by experts qualified by scientific training and experience to evaluate the drug's effectiveness

What is a new drug?

1. A drug that is not generally recognized by qualified experts as safe and effective for use under the condition recommended in the drug's labeling

2. Has not been used "to a material extent or for a material time under the conditions recommended in the labeling"

- Exception would be drugs marketed before 1938 that have been grandfathered in, provided that it is marketed in accordance with the labeling requirements as then existed, would not need an NDA

- Post-1938 drugs can argue that they meet the two requirements, but the FDA has not GRASEd products (exceptions were OTC items) and instead required them to submit an NDA

How can an approved drug become a new drug?

• The drug contains a new substance (e.g., active ingredient, excipient, carrier, coating).

• There is a new combination of approved drugs

• The proportion of ingredients in combination is changed

• There is a new intended use for the drug

• The dosage, method or duration of administration or application is changed

If it's illegal to ship a drug without an NDA, how can manufacturers bypass this?

By applying for an IND following rigorous animal and lab experimentation

Investigation New Drug (IND) Requirements:

1. Drug name

2. Composition

3. Methods of manufacture and quality control

4. Information from preclinical (animal) investigations regarding pharmacological, PK and toxicological evals

5. Information regarding the experience and qualifications of the clinical investigators

• Primary purpose to make sure a drug is safe for humans before starting clinical trials AND to prevent problems in the NDA review

• If the FDA does not reject the IND request within 30 days, human clinical testing may begin

When can a manufacturer start human clinical testing after submitting an IND application?

If the FDA does not reject the IND request within 30 days of submission

The Road to an Approved New Drug Application

Preclinical animal studies

↓

IND

↓

Human Phase Clinical Studies

↓

NDA

↓

FDA approval

Can a manufacturer appeal if the FDA decides to terminate the testing of an IND if there are studies showing that the drug is too toxic under the agency's benefit-risk ratio?

NO! The FDA's determination is final and not subject to appeal or judicial review.

Public Registry of Clinical Trials

NDA sponsors must publish summary information about post-phase 1 clinical trials on a public registry so that healthcare providers and the general public can track the safety and efficacy data generated in the study

Informed Consent (Reading)

• Is required in all three IND clinical phases

• If the study takes place in a institutional setting, the local Institutional Review Board (IRB) must approve the study

• Informed consent is required in WRITING and sign the form for phase 1, 2 and mainly 3. In phase 3, oral consent may be acceptable if the physician says so or if it is preferable.

• Patient consent may not be necessary if it is not feasible or not in the best interest of the patient.

The New Drug Application

• 100k - 200k pages of summary and raw data

• By statute, the FDA has 180 days to act on a completed NDA, but delays are common, so NDAs are prioritized depending on a rating

• Proof of the drug's safety and efficacy, proposed manufacturing process, and benefit-risk ratio generally determine whether the FDA will approve an NDA

• The Prescription Drug User Fee Act has expedited approval times through the collection of fees to hire more reviewers and discourage sponsors from submitting applications until there is a high probability of success

• If the application is disapproved, a hearing is offered

Prescription Drug User Fee Act

This act states that manufacturers must pay a user fee along with each drug that is marketed, facility that manufacturers drugs, and each app from approval.

The money is used to hire drug reviewers and facilitate the drug approval process.

21st Century Cures Act

• Encourages the consideration of novel clinical trial designs and the incorporation of "real world evidence" into the decision-making process

• Requires FDA to consider how patient experience data, including outcomes and preferences, can be used during the approval process

• This Act was passed in large part to streamline and add flexibility and innovation to the drug development and approval process, primarily by creating new clinical trial design options and by accelerating the pathways to market for drugs intended to treat certain serious or life-threatening diseases.

• Created/amended four pathways:

1. Genetically targeted drugs that meet unmet medical needs

2. Antimicrobial-resistant drugs

3. Orphan drug program

4. Rare pediatric diseases

• This law also provides for billions of dollars of additional funding to the National Institute of Health (NIH).

What four pathways did the 21st century cures act amend?

1. Genetically targeted drugs that meet unmet medical needs

2. Antimicrobial-resistant drugs

3. Orphan drug program

4. Rare pediatric diseases

FDA Drug Rating and Classification System

• Number-Letter - determines how rapidly it will proceed through the NDA process and is assigned when the IND request is made and can be changed after that

• Number = Chemical Type (could include multiple numers)

1. New molecular entity

2. New active ingredient

3. New dosage form

4. New combination of compounds

5. New formulation or new manufacturer

6. New indication (drug product previously marked by the same firm)

7. Drug already marketed without an approved NDA

8. OTC switch

9. New indication submitted as a distinct NDA, consolidated with the original NDA after approval

10. New indication submitted as a distinct NDA, not consolidated (allows them to extend the patient)

• Letter = Therapeutic Potential (P, O, S)

- Priority

- Orphan

- Standard

When would a drug be given a rating of P?

• No other effective drugs are available

• It is more effective or safer than the drugs currently used

• It has important advantages such as greater convenience, reduced side effects or improved tolerance or usefulness in special populations

When would a drug be given a rating of O?

• Product treats a rare disease affecting < 200,000 persons in the US

• More than 200,000 people have the disease, but there is no reasonable expectation that the cost of developing and making the drug available in the US will be recovered from the sales in the US

Supplemental New Drug Applications

• After the approval for an NDA, a manufacturer usually may not make any changes in the drug or its production, even the most minor ones, unless it submits for approval a supplemental NDA

• Three procedural categories:

1. "Prior Approval" - changes in any part of the production, ranging from the synthesis of the drug to the manufacturing processes of the drug to most of the labeling of the drug-- FDA must approve first!

- Have lower priority than NDAs and may take years to be approved

2. "Change being effected" - labeling changes that strengthen warnings, or dosage and administration information, or for certain changes in manufacturing methods, facilities and controls-- the sponser can implement changes before the FDA approves it

3. Minor Changes - editorial changes in labeling or changes in container size can be reported in the annual report that the sponsor files to the FDA

Post marketing Surveillance

• Manufacturers are required to maintain and establish postmarketing records and reports under the FDCA

• They must submit to the FDA reports of any serious ADRs and any new information relating to the drug's safety and efficacy

• The FDA then compiles this information into the FDA Adverse Event Reporting System (FAERS) and monitors that data for any safety concerns

Phase IV Studies

• Post-market clinical studies can be used to determine new uses or abuses or to obtain additional safety or efficacy data

• The FDA may require additional clinical trials following NDA approval to assess serious risks if postmarket surveillance is deemed insufficient

- The FDAAA granted this authority

Risk Evaluation and Mitigation Strategy (REMS)

• FDA can require a drug product sponsor to establish special procedures (ex., distribution of a Medication Guide) directed at patient safety

• Used to manage known or potential serious risks of a product

• Can be required during the pending NDA and or even postmarket

Postmarket Labeling Addition

• The FDAA provided the FDA with the authority to compel safety-related labeling changes when the FDA becomes aware of a serious drug risk it believes should be included in the labeling

Sentinel Initiative

A proactive surveillance system designed to detect early signs of medication risk and safety problems by scouring through EHRs and insurance claims.

Kefauver-Harris Amendment

• Also known as the "Drug Efficacy Amendment".

• Required drug manufacturers to provide proof of the effectiveness and safety of their drugs before approval .

• Required drug advertising to be more closely regulated and disclose accurate information about side effects

Abbreviated New Drug Application (ANDA), paper NDAs and PTRA

• To lighten the burden of the FDA when generics were considered new drugs under DESI and therefore required proof of efficacy, meaning the FDA now had to look over thousands of NDA applications.

• An ANDA could be submitted by generic companies instead, and under it, proof of safety and efficacy was NOT required. Only proof of bioequivalence and proof of acceptable manufacturing methods and controls were needed.

• However, the ANDA applied to only the 1938 -1962 drugs, and post-1962 drugs were left having to apply for NDAs, which were much more extensive

• As a band-aid to that problem, "paper NDAs" were allowed where drugs could use research from the innovator drugs to establish safety and efficacy, but this only helped out a few generics

• The Patent Term Restoration Act (PTRA) was the ultimate solution for those post-1962 drugs and allowed them also be able to also submit ANDAs (not just drugs from 1938 - 1962)

DESI Review

• Pre-Kefauver-Harris Amendment (1962) and DESI (1968), generics weren't considered new drugs that required proof of efficacy, but following DESI, all of those generics post-1938 needed to submit NDAs (and later aNDAs) to prove efficacy

• Drug Efficacy Study Implementation (DESI) was a FDA (U.S. Food and Drug Administration) process initiated in the 1960s following the Kefauver-Harris Amendment to evaluate the effectiveness of drugs approved for safety but not proven effective, a category of drugs approved before 1962. The DESI process involved reviewing existing information, publishing findings on the efficacy of drugs, and categorizing them as "effective," "ineffective," or "needing further study" by the National Academy of Sciencies National Research Council. This led to enforcement action against ineffective drugs, removing them from the market or requiring manufacturers to provide proof of effectiveness.

Patent Term Restoration Act of 1984

• Allowed post-1962 generics to be able to submit ANDAs

• Allowed patent extensions

• Market exclusivity for manufacturers for...

- New Chemical Entity (5 years)

- New Indications, Dosages or Strengths (3 years)

• Established 505(b)(2) NDAs

In order to ultimately obtain approval for an ANDA, the generic manufacturer must make a patent certification:

Four types:

1. NDA holder never filed information on a patent to the FDA

2. Patent already expired

3. The patent will expire soon

4. That the patent is invalid or will not be infringed by the manufacture, use, or sale of the generic applicant's drug

- Tricky since if the patent owner sues the generic applicant, the FDA cannot touch the ANDA application for 30 months

- But....the law awards 180 days of market exclusivity for the first generic application to file an ANDA containing a paragraph IV certification

"Authorized Generic"

When an innovator drug manufacturer produces a generic version of its brand-name product, which does NOT require an ANDA since the FDA considers it the same product as the original NDA.

This means that the innovator manufacturer can produce the generic and compete directly with a generic manufacturer who filed a successful paragraph IV certification with its ANDA.

Product Hopping

When a product nears its patent expiration, the manufacturer will make a product change and secure an additional patent. Then they will extensively market the new product and encourage patients to switch over.

Pliva and Mensing Decisions

• Currently at limbo where is an innovater drug injures a patient, they are required to update their labeling using the "change being effecting" sNDA. But, if a generic hurts a patient, they were NOT required to change their labeling since the law requires that the labeling of a generic drug be the same as that of the innovater drug.

• The FDA has delayed making a final rule on this.

505(b)(2) NDAs

• Established by the Drug Price Competiton and Patent Term Restoration Act (PTRA)

• Allowed a manufacturer to rely, at least in part, on published safety and efficacy data and/or the FDA's findings for a previous approved drug, therefore reduce the costs to a manufacturer in holding clinical trials

• Could be used to receive approval for new indications where now only efficacy data was needed OR a generic manufacturer might choose this route of applciation instead of a full NDA when the generic cannot use an ANDA due to significant cahnges from the reference product

• Depending on the extent of the changes from the reference product, a manufacturer could be granted 3 - 5 years of market exclusivity

Drug Competition Action Plan

• The goal is to institute new policies aimed at bringing more competition to the drug market, most notably improving the efficiency of the generic drug approval process.

• Policies designed to bring complex generic drugs to market more quickly

• Closed loopholes used against generic manufacturers

OTC Drug Review

• The Kefauver-Harris amendement applied not only to Rx drugs, but also OTC, so in 1972, the FDA began reviewing the efficacy of those OTC products from 1938 - 1962

• Approves drugs on the basis of therapeutic category and conformance to a monograph rather than on a drug by drug basis like prescription drugs

• Process:

1. FDA appoints advisory review panels of qualified experts to consider drugs by class (ex. analgesics, antacids) and make recommendations to the agency

2. Recommendations published in the Federal Registry

3. Accepts public comment

4. Agency publishes proposed rule in the Federal Registry

5. Then, the agency publishes a monograph, identifiying which active ingredients are generally recognized as safe and effective (GRASE) and, this, may be marketed and specifies labeling

6. New OTC products that conform to the published monograph requirements may be marketed without FDA approval

7. If an OTC manufacturer does not conform, they need to submit an NDA

• Final monograph places the reviewed ingredients into one of the tree categories:

1. Category I: Product GRASE and not misbranded

2. Category II: Product are not GRASE or that are misbranded

3. Category III: Data is unsufficient to classify

• The FDA has allowed Category III drugs to be market pending review, despite litigiation and safety concerns

Additional Condition for Nonprescription Use (ACNU)

• Intended to broaden the types of nonprescription drug products available to consumers, allowing the ACNU to enable self-selection and appropriate use of a product by the consumer without the oversign of a healthcare practioner

Unapproved Drug Initative (UDI)

• Was established under the FDA's 2006 Compliance Policy Guide (CPG)

• Describes the FDA's enforcement actions against the 1000s of illegal unapproved products

• There are many reasons why a drug both legal and illegal unapproved drug products exist on the market

- Market prior to 1938; it is a generic drug marketed between 1938 and 1962 thta escaped DESI reciew, pending DESI review or just remained on the market despite adverse DESI review; it is a nongeneric drug marketed between 1938 and 1962 that the FDA felt was not a new drug; it is a drug marketed by an unscrupulous manufacturer who tentionally avoided FDA approval for profit purposes

• The FDA usually priortizies enforcement of marketed unapproved drugs that present safety risks

• In 2011, the CPG said that illegally manufactured drugs would be subject to immediate enforcment action without prior notice

• In 2020, the UDI was terminated to deal with the rising cost of prescription drugs

• In 2021, it was reinstated

• Pharmacists should dispense approved products (use Drugs@FDA website)...duh

Parallel Track Policy

• Sponser must submit a protocol to describe use of the drug

• Previously, FDA policy has restricted medication treatment with an IND to those drugs in phase 3

• A court case tried to expand access to Phase 2 and had succeeded, but then that ruling was reversed

• Ultimately, the courts under the FDA Expanded Access Program/compassionate use allowed people to have access to IND in phase 1

is the right to an IND constitutional?

No.

Expedited approval of Drugs Intended to Treat Serious or Life Threatening Illnesses

1. FAST TRACK: Used to treat a serious illness and demonstrates the potential to address unmet medical need

- Need Phase IV studies + submission of promotional materials 30 days before dessmination

2. BREAKTHROUGH THERAPY: Used to treat a serious illness and demonstrates substantial improvement on a clinically significant endpoint compared with available therapies

- Need Phase IV studies + submission of promotional materials 30 days before dessmination

3. ACCELERATED APPROVAL: Used to treat a serious illness and demonstrates substantial improvement on a surrogate endpoint compared with available therapies

4. PRIORITY REVIEW: Drug intended for serious condition and the drug provides a significant improvement in safety or effectiveness

Biologics

• Products derived from living organisms, including viruses, therapuetic serums, toxins, antitoxins, vaccines, blood and blood components

• Require premarket approval from the FDA, BUT ARE LICENSED UNDER THE Public Health Service Act (PHSA)

- The FDA will approve the license upon demonstration that the product is safe, pure, and potent

• Biosimilars approval process established by the Affordable Care Act, and documented in the Purple Book

Biologics Price Competition and Innovation Act (BPCIA)

• This act establishes generic approval pathway for biologics (BLA) unde the ACA by the FDA

• Biosimilar can be expected to produce the same clinical results as the reference product without any greater risk

• 12-year marketing exclusivity to the innovater product

• ACA requires a biosimilar manufactrer to give notice ot hte brand name manufacturer 190 days prior to hte "first commerical marketing"

Purple Book

A database that contains information about all FDA-licensed biological products regulated by the Center for Drug Evaluation and Research (CDER), including licensed biosimilar and interchangeable products, and their reference products.

MedWatch

• This is the FDA reporting service for adverse effects that occur from use of approved drugs.

• Pharmcies have an obligation to notify patients of the MedWatch phone number via five methods

Medical Devices

• Comprehensive system of device regulation that includes device classification, premarket testing, and standards of performance

• Three Classes:

1. Class I Devices - least potential harm to users and require "general controls." Includes needles, scissors, examination gloves, stethoscopes, and toothbrushes.

2. Class II Devices: General controls alone are insufficient and must meet specific performance standards. Includes insulin syringes, infusion pumps, thermometers, diagnostic reagents, tampons, and electric heating pads.

3. Class III Devices: Must have premarket approval because they are life-supporting or life-sustaining, or they present a potential unreasonable risk of illness. Includes pacemakers, soft contact lenses, and replacement heart valves.

• Medical device forms must report to the FDA any death or serious injury that may be related ot their product

• Medical devices have a "unique device identifier" (UDI)

General Controls

Require device manufacturers to register their facility and list their products with the FDA, provide premarket notification in some cases, maintain records and reports, and adhere to the CGMP

Expedited Access Pathway (EAP)

A 2015 voluntary, expedited approval process for devices that demonstrate the potential to address unmet medical needs for life-threatening or irrevisibly debilitating diseases or conditions

Cosmetics

• Are not subject to premarket approval; however, they are subject to certain misbranding and adulteration laws and the FDA can take regulatory action against them

They do not need to conform to CGMP or register with the FDA

• Some cosmetics have specific warning statements

• Can be misbranded for several reasons

• Can be adulterated for many reasons