Regulatory Basics

2009 Biologics price comp and innovation act (BPCI Act)

created an abbreviated approval pathway for biosimilars

1962 kefauver-harris amendments to the FD&C act

tightened safety stds and introduced requirements that drugs must be effective

1997 FDAMA

Food and Drug Administration Modernization Act (FDAMA): include Fast Track Designation

True or false: "The advice of advisory committees is binding on the FDA"

This statement is mostly inaccurate. As reported in the 2013 McKinsey Center for Government FDA Advisory Committee Outcomes report, the FDA typically follows the advisory committee recommendation. Of the 49 recommended approvals, the FDA denied approval to 6 of the products. Likewise, of the 16 not recommended, 2 were ultimately approved by the FDA.

1938 Food, Drug, and Cosmetic Act

introduces safety standards

exclusivity

-award/reward of marketing protection of 3 to 5 yrs for innovation development to an existing product (ie new uses, strengths) -6 months for pediatrics

The current Prescription Drug User Fee Act (PDUFA) iteration calls for FDA to review and act upon 90 percent of standard NDAs within ____ months and 90 percent of priority applications within ____ months.

10, 6

patent protection

17 years from the date the patent was issued or 20 years from the date submitted to the patent office, not FDA approx 12 years of marketing protection

Bioequivalence: Regulatory Definition

21 CFR 320.1 (e) •The lack of a difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

2007 FDAAA

: Food and Drug Administration Amendment Act (FDAAA) User fee for drug and device

How is 'unmet medical need' defined?

A condition whose treatment or diagnosis is not addressed adequately by available therapy, including - Immediate need for a defined population (ie, to treat a serious condition with no or limited treatment) - Longer-term need for society (eg, to address the development of resistance to antibacterial drugs)

U.S. Evidentiary Standard for Approval

A drug or biological product approved in U.S. must: • Demonstrate substantial evidence of effectiveness/clinical benefit (21CFR 314.50) Evidence of effectiveness [PHS Act, 505(d)] • Evidence consisting of adequate and well-controlled investigations on the basis of which it could fairly andresponsibly be concluded that the drug will have the effectit purports to have under the conditions of use prescribed,recommended, or suggested in the labeling

what is the orange book?

All FDA approved drug products listed (NDA's, OTC's & ANDA's) • Therapeutic equivalence codes è "A" = Substitutable è "B" = Inequivalent, NOT Substitutable • Expiration dates: patent and exclusivity • Reference Listed Drugs/brand drugs identified by FDA for generic companies to compare with their proposed products

what is advertising?

All activities used by the sponsor or license holder to create an interest in their product Just a note: Pharmaceutical advertising is regulated by the FDA. Over the counter (OTC) advertising is regulated by the FTC

1. Would the advertisement below be regulated by the FDA? Why or why not?

Although it is obviously material produced by Vertex Pharmaceuticals, it would not be regulated by the FDA. This material falls under the disease awareness category and makes no claims to a specific product.

What is the objective of an end-of-phase 2A (EOP2A) meeting with the FDA?

An EOP2A meeting with the FDA is for first-in-class innovative drugs and fast track drugs and the overall goal is to ensure the study designs are acceptable to the FDA to support dose selection for later trials. Nonclinical data can be evaluated for completeness, the size of the safety database, special population considerations, and phase 3 study design can be evaluated during the EOP2A meeting. so that the sponsor can achieve the indication / label claim desired. More specifically, EOP2 meetings can be CMC-specific wherein attendees discuss starting material definitions, impurities, stability protocol, analytical procedures, clinical trial formulation versus market formulation, and novel dosage forms.

extent is measured by what?

Area Under Curve (AUC) • AUC0-t is a measure of the total exposure of drug to the body up to the last sampling time • AUC0-inf is a theoretical measure of the total exposure of drug to the body from administration until all the drug is eliminated

1984 Hatch-Waxman Act

Created an abbreviated mechanisms for approval of generic drugs by stating that pre-clin and clinical testing does not have to be repeated allowed generic firms to rely on findings of safety and efficacy of innovator drug after expiration of patents and exclusivities allowed patent extension and exclusivities to innovator firms

waivers of in vivo study requirements for bioequivalence study

Criteria (21 CFR 320.22) • In vivo bioequivalence is self-evident • Parenteral solutions • Inhalational anesthetics • Topical (skin) solution • Oral solution • Different proportional strength of product with demonstrated BE

When is an IND required?

If a clinical trial meets three criteria: 1. The research involves a drug 2. The research is a clinical investigation 3. The clinical investigation is not otherwise exempt

When is an not IND required?

If six criteria are met: 1. The drug product is lawfully marketed in the US 2. There is no intent to report the investigation to FDA as a well controlled study 3. The investigation is not intended to support a significant change in drug advertising 4. The investigation does not involve a route of administration, dose,patient population or other factor that significantly increases the risk associated with the use of the product 5. The investigation is conducted in compliance with the requirements for review by an IRB and with the requirements for informed consent 6. The investigation is not intended to promote or commercialize the drug product

What are the NDs?

Neglected diseases are diseases affecting populations in mainly low-/middle-income countries (LMICs), and are a leading cause of mortality, chronic disability (morbidity) and poverty

Define "postmarketing requirement". Using resources reviewed in class, identify and list below the two postmarketing requirements for Etelcalcetide under the Pediatric Research Equity Act (PREA).

Postmarketing requirements are commitments made by a sponsor that typically will assess safety and risk is specific populations or long-term use of the product. Under PREA, the sponsor is required to conduct an adequate and well-controlled study in patients with secondary hyperparathyroidism receiving hemodialysis that are aged 2 to 17 as well as aged 1 month to 2 years. In addition, the sponsor is required to conduct a comparative PK/PD study evaluating the drug in adults and pediatric subjects.

What is the FDA's mission?

Protecting public health by: 1. Assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, the nation's food supply, cosmetics, and products that emit radiation. 2. Helping to speed innovations that make medicines more effective, safer, and affordable; and by helping the public get the accurate, science based information they need to use medicines and foods to maintain and improve their health. 3. Regulating the manufacturing, marketing, and distribution of tobacco products to protect the public health and to reduce tobacco use by minors. 4. Playing a significant role in the nation's counter terrorism capability by ensuring the security of the food supply and by fostering development of medical products to respond to deliberate and naturally emerging public health threats

Adequate and well-controlled study

Study should "distinguish the effect of a drug from other influences, such as spontaneous change...,placebo effect, or biased observation" Must incorporate generally accepted scientific principles for clinical trials Well-controlled studies of adequate design must show effectiveness, ordinarily a statistically significant effect on a clinically meaningful endpoint, usually replicated, as a basis for approval.

Compare and contrast PREA and BPCA

The Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA) are both products of the changing sentiments on pediatrics in clinical studies. For quite some time, the societal thought was that children should be protected from clinical studies. The tides have changed and now children should be represented in clinical studies. PREA mandates a pediatric study to be executed if the adult and pediatric diseases share the same indication (excluding orphan indications). BPCA is voluntary study in pediatric indications and is incentivized with 6 months of market exclusivity. Both acts cover drugs and biologics and share an overall goal of providing pediatric information and drug labeling while encouraging appropriate use in children. PREA and BPCA have same goal; providing pediatric information in drug labeling to encourage the appropriate use of drugs in treating pediatric patients. PREA studies are mandatory and required only for indication under review. PREA exempts for orphan indications. In contrast, BPCA studies are voluntary and offer 6 month exclusivity and studies may expand indications. BPCA can study orphan indications. Both PREA and BPCA, results must be in labeling.

When available treatment exists, how can a new drug satisfy an 'unmetmedical need'?

Therapy associated with improved efficacy - Superiority of new treatment on efficacy/serious outcomes of condition - Effect on patients unresponsive to other therapies Therapy associated with improved safety - Effect on patients who are unable to tolerate other therapy Available treatments are approved under accelerated approval regulations and have not been confirmed by post-approval studies

What two countries allow direct to consumer pharmaceutical advertising?

US and New Sealand

Fast Track

an approval program is intended for use in drugs treating serious or life-threatening conditions and that address an unmet medical need. The program facilitates expedited review of new drugs by allowing more frequent meetings and rolling NDA. In addition, these drugs may be given Priority Review status and are eligible for accelerated approval. ● A drug intended to treat a serious condition, and clinical or non clinical data demonstrate it has the potential to address an unmet medical need ● Can request anytime after IND submission to pre-NDA/BLA meeting. ● More frequent interactions/meetings with FDA Rolling review (Complete sections of NDA/BLA (CMC, preclinical, clinical) can be submitted ahead of final submission components)

rate is measured by what?

cmax • Cmax is the maximum observed concentration • Cmax tends to have higher variability • Need adequate sampling time-poin

1906 Pure Food and Drug Act

establishes regulation of food and drugs

2012 FDASIA

expands the FDA'sauthorities and strengthens the agency's ability to safeguard and advance public health by:• Giving the authority to collect user fees from industry to fund reviews of innovator drugs,medical devices, generic drugs and biosimilar biological products;• Promoting innovation to speed patient access to safe and effective products• Increasing stakeholder involvement in FDA processes• Enhancing the safety of the drug supply chain

Accelerated Approval

granted to drugs that have surrogate endpoints that are reasonably likely to predict clinical benefit. Eligibility criteria include treatments for serious or life-threatening diseases that address an unmet medical need. The main incentive is that these drugs can make it to the market and to patients faster. ● A drug that treats a serious condition and generally provides a meaningful advantage over available therapies ● The drug demonstrates an effect on: ○ A surrogate endpoint that is reasonably likely to predict a clinical benefit ○ A clinical endpoint that can be measured before irreversible morbidity or mortality(IMM) ○ Meaningful advantage over available therapy or lack of alternative treatment ● Drug granted AA must meet the same statutory standards for safety and effectiveness as those granted traditional approval ● Postmarketing requirement to demonstrate clinical benefit All advertising and promotion for AA product must be pre-cleared by FDA (at least 30 days notice prior to use material post-approval)

Priority Review

shortens FDA review time by roughly 4 months for both NDA/BLAs as well as supplemental NDA/BLAs. This is granted to drugs that have potential to provide significant advances and the incentive is that these drugs can make it to the market and patients faster. ● A drug that treats a serious condition or demonstrates potential to be a significant improvement in safety or effectiveness ● Can include a request for priority review in cover letter sent with original NDA, BLA or efficacy supplement ● 6-month NDA/BLA review clock For NMEs, per FDASIA, 2-month filing review period included prior to start of Priority/Standard review period.

Purpose of Bioequivalence

• Therapeutic equivalence (TE) • Bioequivalent products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring • The most efficient method of assuring TE is to assure that the formulations perform in an equivalent manner Comparison between a test and reference drug product • Generic drug vs. reference listed drug (i.e. brand name drug or innovator drug) • Bioequivalence is not only for generic drugs • commercial formulation vs. clinical trial material • drug product changed after approval vs. drug product before change

washout period

time when patient is not getting any drugs to allow drug to clear out between study periods. usually about 5 half lives (take any number and divide it by 2, 5times)

generic drug lableing

• "Same" as brand name labeling • May delete portions of labeling protected by patent or exclusivity • May differ in excipients, PK data and how supplied

what is a biosimilar?

• A biologic product that is "highly similar" or interchangeable with a biologic product • Established in US by the Biologics Price Competition and Innovation Act of 2009 • No clinically meaningful differences in terms of safety, purity, and potency • Available in same dosage strength and form • Manufactured according to current Good Manufacturing Practice (cGMP) regulations

Competitive Intelligence

• A process which gives insights into what might happen • Requires analysis (assumptions) • Selection, collection, interpretation and distribution of information that has strategic importance • Gather a wide range of information in a systematic, legal manner to make predictions of competitive landscape in order to select targets and position drugs

when can a generic drug be marketed?

• After patent & exclusivity protection ends, or • Patent owner waives its rights, and • FDA requirements are met

narrow therapeutic range (NTI) drugs

• Drug Products that are subject to therapeutic drug concentration or pharmacodynamic monitoring • Examples are: Digoxin, Lithium, Phenytoin, Warfarin, Immunosuppressive medications for use in transplant (cyclosporine, tacrolimus, etc) • A "small" difference between effective concentrations and toxic concentrations • For example, the goal Cmin (trough concentration) in kidney transplant taking tacrolimus (an immunosuppressive drug) is 8-10 ng/mL. • Traditional bioequivalence limit of 80-125% is unchanged for these products

FDA approval process for biosimilars

• Must prove that the product is "highly similar," notwithstanding minor differences in clinically-inactive ingredients • No clinically-meaningful differences between the biological product and the reference product in safety, purity, or potency • The risk of switching between the biosimilar product and reference product must not be greater than the risk of using only the reference product consistently

bioequivalence assumptions

• Plasma concentration data are a reasonable surrogate for concentrations at active site • Rate and extent of absorption are similar: no significant difference in exposure to drug • Can extrapolate safety and efficacy data from reference product to test product

What are the Basic Generic Drug Requirements?

• Same active ingredient(s) (inactive ingredients may vary) • Same route of administration • Same dosage form • Same strength • Same indication • Manufactured under the same strict standards of FDA's GMP regulations required for innovator products • Same batch requirements for identity, strength, purity and quality • Inactive ingredients already approved in a separate NDA

Phase 3

○ The most extensive (and expensive) testing ○ Fully assess safety, efficacy, dosage in large group (100~ 1000s) of patients with the specific disease to be tested ○ Diverse groups of patients with the condition ○ Comparisons between the new treatment and a placebo and/or the standard treatment ○ Help better understand the drug's safety and uncover AEs.

Phase 1

○ First-in-human Study ○ Purpose ■ Estimation of initial safety and tolerability: safe dose range, AEs ■ Determine PKs: ADME, half-life, characterize metabolites ■ Assessment PDs: Mechanism of action in human ■ Early assessment of activity: potential for therapeutic effectiveness ■ 20~100 healthy subject or patient (e.g. cancer; typically not ethical to enroll healthy volunteers in Phase 1 study because of its high toxicity); often single ascending dose (SAD) ○ Focus: Safety

pediatric indicators

○ Generally, based on data from studies in ■ A pediatric population only ■ Both adult and pediatric populations ■ Adults, with supporting data in a pediatric population (e.g. safety, PK data)

IND

○ Major milestone between preclinical and clinical ■ Submission with which a drug sponsor alerts the FDA of its intention to conduct clinical studies with an investigational drug

2007 PREA

○ Pediatric Research Equity Act (PREA) to encourage more research, development and treatment for children. MANDATORY

1992 PDUFA

○ Prescription Drug User Fee Act (PDUFA): Pharmaceutical companies need to pay user fees to proceed NDA review regardless to approval ■ User fee is used to hire more people to keep the review period. Orphan designation allows companies to waive the User fees.

● Off-label Use of Drugs

○ The use of a drug outside of an approved FDA indication ○ "Off-label" does not imply an improper, illegal, contraindicated, or investigational use of a drug

benefits of generic competition

1. meet patient demand 2. keep insurance premiums down 3. save consumers billions yearly generic pharmaceutical products are used to fill nearly 2.6 billion prescriptions every year

Current FDA initiatives

1) Advancing precision medicine 2) New approaches for analyzing efficacy of oncology drugs 3) 21st Century Cures Act and pediatric development initiatives

Types of Promotions

1. Disease Awareness 1. Not intended to be "treatment awareness" 2. Not considered pharmaceutical advertising and not regulated by FDA 2. Reminder Ad 1. Regulations specifically exempt from disclosure requirements 2. Includes name of the product 3. No representations beyond • Dosing form • Packaging • Price information 3. Product Claim Advertisements 1. Advertisement that provides: Medication name / At least one indication/ Product safety information / Product benefit information 2. Advertisement that provides :Medication name / At least one indication / Product safety information / Product benefit information 4. Corporate PR Materials

● Comparison between legal & compliance function

1. Legal- Advise and protect the organization from legal problems , Defend the actions of the organization 2. Compliance- Prevent and detect legal misconduct , Implementing and monitoring compliance programs and internal systems , Fostering a culture of accountability (especially for senior management)

what is compliance?

1. Written standards, policies and procedures 2. Compliance "administration" (e.g. compliance managers, officers, directors) 3. Communications, training and education 4. Monitoring and auditing 5. Reporting and investigation 6. Enforcement and discipline 7. Response and prevention

brand name drug NDA requirements

1. chemistry 2. manufacturing 3. controls 4. labeling 5. testing 6. animal studies 7. clinical studies 8. bioavailability

generic drug ANDA requirements

1. chemistry 2. manufacturing 3. controls 4. labeling 5. testing 6. bioequivalence*

Describe how an ANDA differs from an NDA

A New Drug Application (NDA) is for an innovator drug while an Abbreviated New Drug Application (ANDA) is for a generic drug product and was created from the Hatch-Waxman Act in 1984. Both an NDA and an ANDA require labeling, pharm/tox, CMC, microbiology, inspection and testing. An NDA also requires animal studies, clinical studies, and bioavailability—the most expensive part of drug development. In lieu of these additional studies, an ANDA only requires a bioequivalence study. More specifically, a generic is deem bioequivalence if the 90% confidence interval for the ratio for AUC and Cmax of test and reference products are with in 80% to 125%. Bioequivalence study design typically includes health volunteers, a single dose, and administering the drug while fasted. It is relevant to note that with this study design, it is assumed that plasma drug concentration data are a reasonable surrogate for concentrations at the site of activity.

1. Explain how the Tropical Disease Priority Review Voucher (PRV) program is intended to stimulate drug development for tropical diseases.

A Tropical Disease Priority Review Voucher (PRV) guarantees review in 6 months (over standard 10 month review), and if it is also an orphan drug, there are no filing fees. The entitlement is only granted to new molecular entities and excludes new indications for previously approved drugs. While not likely to stimulate drug development for tropical diseases, it is important to note that this voucher can be transferred to another sponsor, and the additional 4 months of market exclusivity has clear monetary value. In 2014-2015, PRVs were sold for $68 million to $350 million.

determining bioequivalence

Compare Test vs. Reference • Ratios for AUC and Cmax of test and reference products in the same patients with a washout period separating the two • Determine 90% confidence interval for ratios • Criteria for log-transformed data: • 90% Confidence Interval (CI): 0.8 to 1.25 (80% to 125%) • Conclude that two treatments are not different from one another if the 90% confidence interval of the ratio of a log-transformed AUC and Cmax falls completely within the range 80-125%. • Conclude that the two treatments are "not different" from one another. • Do not conclude that they are the "same". • However, if the 90% confidence interval falls outside the 80-125% range, we conclude that the two treatments are different from one another. • Note that the range is arbitrary, and essentially reflects belief that differences in systemic drug exposure up to 20% are not clinically significant

Breakthrough Therapy Designation

Drugs designated as this are intended to treat serious conditions which also have preliminary clinical evidence of substantial improvement over existing therapies. In addition to the incentives associated with Fast Track designation, Breakthrough Therapies are granted intensive guidance and FDA commitments involving senior managers. ● A drug intended to treat a serious condition, and preliminary clinical evidence shows the drug may demonstrate substantial improvement on a clinically significant endpoint over available therapies ● Commitment from FDA involving senior managers including cross-disciplinary project lead to serve as a liaison between members of the review team ● Intensive guidance on an efficient drug development program as early as Phase 1 Review Eligible for rolling review (same benefit as FT) and may be eligible for Priority Review

2012 GDUFA

Generic Drug User Fee Act(GDUFA) A law designed to speed access to safe and effective generic drugs to the public, and reduce costs to industry. • Up until October 2012, the law only required user fees for firms submitting NDAs (e.g. PDUFA) As of October 1, 2012, under GDUFA, all firms that manufacture human generic drug products, and active ingredients for human generic drug products, that are distributed in U.S. commerce are subject to FDA user fees. GDUFA fees increase the ability of the FDA to perform critical program functions and to reduce costs considering the reduced review timelines

Explain why regulatory harmonization in drug development is important for the pharmaceutical industry.

Harmonization, such at the International Conference on Harmonization (ICH), can aid in reducing burden on the pharmaceutical industry of having to adhere to multiple regulation requirements. This can facilitate medicines that are developed and registered in the most resource-efficient manner while adhering to safety, efficacy and quality standards. Harmonization can also protect public health interests across the globe by creating an opportunity for regulatory authorities and industry leaders to discuss scientific issues related to requirements. It is very difficult for regulations, guidance, and policy to keep pace with scientific innovation. Future requirements for new technologies can be adopted globally. Mainly, harmonization allows companies to reach more markets.

FDA is supporting the development of precision medicines. Describe what precision medicine is, provide an example of this, and describe why a companion diagnostic might be needed to accompany a precision medicine.

Precision medicine is a relatively new development in the pharmaceutical industry that was catalyzed by the relative ease of gene sequencing. With this technology, disease pathways and targets can be better understood and linked to clinical outcomes. Moreover, drugs can be targeted patients that will have optimal responses to therapies. Development of accurate companion diagnostic is integral to successful implementation of precision medicines because they can identify patients who are most likely to benefit or who are most likely to suffer from an adverse reaction. An example of precision medicine can be seen with Brineura (cerliponase alfa) for treatment of CLN2 type Batten disease. Use of brineura is contingent upon TPP1 biomarker status in patients.

How has thinking and policy changed in the past ~ 15 years regarding pediatric drug dev?

Previously: Children must be protected from clinical research Now: Children must be protected through clinical research

Purpose of the Pre-IND Meeting

Primary purpose: Review and reach agreement on the design of animal studies needed to initiate human testing

2002 BPCA

The Best Pharmaceuticals for Children Act (BPCA) - encourage drug companies to develop drugs for children. VOLUNTARY 6 mo exclusivity

Define "refuse to file" in the context of an NDA or BLA submission and give an example of when this may occur.

The FDA can ___________________________ a submitted application if it is inadequate or incomplete. In this scenario, the FDA can inform the sponsor sooner than if they were to review the submission completely and issue a complete response letter. The sponsor can resubmit later. An example of a deficiency that would cause the FDA to take this action would be if it had been previously determined and communicated that more than a single adequate and well-controlled trial was to be executed, and the NDA/BLA was submitted with only one trial.

differences between the FDA and EMA

There are many big differences between the FDA and the EMA. Aside from the fact that the EMA represents 28 countries and 24 languages (FDA is one country, one language), a major difference is that the FDA regulates and approves drugs for the market whereas the EMA evaluates and provides opinions to the EC. In general, the FDA is more open to meetings (they are strongly encouraged) and they provide free scientific advice allowing communication at any time. CHMP requires a fee for scientific advice, which can be anywhere from $15,000 to $45,000, and communication is only possible at specific times. Meeting minutes are another area of clear definition between the two governing bodies. For the EMA, minutes are provided by company, not the CHMP/SAWG. In the US, the FDA provides official meeting minutes. The two organizations have differing orphan drug incentives as well. In the FDA, orphan drug status can be granted if a disease has <200,000 patients in the US or if development costs plus reasonable profit within 7 years post-approval not expected to be recovered. In Europe, orphan drug status is granted if the disease prevalence is <5 in 10,000 or if the product would be unlikely to geneate sufficient return of investment. Moreover, the disease must be serious / chronic / life-threatening with no satisfactory treatments. Orphan drug incentives in the US include 7 years of market exclusivity with no user fee while market exclusivity in the UE is 10 years with some reduction in fees. 1. Regional difference: the number of country, FDA regulates drug and biologics while EMA evaluates them. 2. Clinical trial Application EMA: Clinical Trial Application (CTA), for individual studies, to be submitted to national competent authority (CA) and ethics committee (EC) for each study. FDA: 1 IND for multiple clinical studies 3. CHMP vs. FDA scientific advice CHMP: request on a voluntary basis, limited opportunities for interaction between CHMP and company, fee for advise, one main meeting type FDA: Meeting strongly encouraged by FDA, Early, frequent and ongoing dialogue between FDA and company, free advise, three types of meeting (A,B, and C) 4. Meeting minutes CHMP: Company provide meeting minutes but final advice is written advice. Clarify ambiguity or disagreements with advice coordinator ASAP. FDA: FDA meeting minutes are only official minutes. Clarify any disagreements with FDA ASAP. 5. Orphan drug incentives EMA: Market exclusivity of 10 years, Fee reduction, Direct access to centralized procedure, Local national incentives, Separate licenses and tradename for orphan and non-orphan. FDA: Market exclusivity of 7 years, NDA/BLA not subject to a drug user fee unless the human drug application includes an indication for other than rare disease or condition, Tax credit for qualified clinical costs undertaken in the USA, Orphan and non-orphan on same license.

What are the benefits of FDA User Fee Programs (e.g. PDUFA, GDUFA, BSUFA, etc.) for the pharmaceutical and biotechnology industries?

This act provides resources to the FDA to accelerate review applications. The fee is waived or reduced for orphan drugs, which affords an incentive for pharmaceutical and biotechnology companies.

A pharmaceutical company submits a meeting request for a Type B, pre-IND, face-to-face meeting. One of the proposed questions that the company includes in their meeting request is: "What should our starting dose be in our Phase 1 trial?" Is this an appropriate question to ask the FDA in a formal face-to-face meeting? Why or why not?

This is not an appropriate question to ask the FDA in this setting because it is open-ended. Every interaction with the FDA is critical and asking a vague question like this could be detrimental to the success of the drug development process. Using preclinical studies, the company should already have an idea of the starting dose. It might be more appropriate to present a position (i.e. dose range) in detail, explain the company's position, and ask if the FDA agrees. In addition, the company should have fall back positions available.

Describe how clinicaltrials.gov may be used in competitive surveillance

can be used for database mining to glean who else is conducting a clinical trial, how far along they are in the development (enrolling, completed, phase 1-3), as well as study specifics (number enrolled, endpoints). The website also shows which trials have been stopped, which may be because of failure/futility or success.

generic drug user fee act (GDUFA)

• a law designed to speed access to safe and effective generic drugs to the public, and reduce costs to industry. • Up until October 2012, the law only required user fees for firms submitting NDAs (e.g. PDUFA) • As of October 1, 2012, under GDUFA, all firms that manufacture human generic drug products, and active ingredients for human generic drug products, that are distributed in U.S. commerce are subject to FDA user fees. • GDUFA fees increase the ability of the FDA to perform critical program functions and to reduce costs considering the reduced review timeline

Bioequivalence study deisgn (typical)

• healthy volunteers • single dose, two-way crossover • administer drug under fasted conditions • strength of the test drug chosen • sampling time • protocol deviations • adverse event monitoring • if fed study: high fat, high calorie bfast

● FDA Guideline

○ "Good Guidance Practices": involve dissemination of draft, public comment, potentially workshops and public meeting, final guidance ○ Not binding on outside parties or FDA

what is a drug?

○ (A) Articles recognized in the Official United States Pharmacopoeia, Official Homeopathic Pharmacopoeia of the United States, or Official National Formulary, or Any Supplement of Any of Them ○ (B) Articles Intended for Use in the Diagnosis, Cure, Mitigation, Treatment, or Prevention of Disease in Man or Other Animals ○ (C) Articles Intended to affect the Structure or Any function of the body of Man or other animals ○ (D) Articles intended for use as a component of any article specified in clause (A), (B), (C) of this paragraph

1992 ICH

○ : International Conference on Harmonization (ICH) - Major effort to harmonize drug regulation across the countries ■ But some differences between countries also exist (e.g. In Japan, it is necessary to need additional clinical trial for Japanese population because of racial difference)

Phase 4

○ Can be mandated by FDA as Post Marketing Requirement (PMR) ○ May be performed to learn more about AEs and long-term risks and benefits ○ May evaluate different formulations of a drug or test new indications

who leads FDA?

○ Commissioner: appointed by the President, Confirmed by the Senate, Insulated from Politics

● Post-marketing surveillance

○ Company must continue to report new findings and problems after drug approval because rare adverse events which may not be seen during trials ○ Healthcare providers/customers can report new findings to the company or FDA. (Medwatch)

● Orphan Drug (OD) Designation

○ Eligibility ■ For rare diseases, <200,000 patients in the United States. ■ Drugs that cannot recover the cost of development by sales. ○ Provisions ■ 7 years of marketing exclusivity. ■ Tax incentives-Deduct 50% of clinical trial costs. ■ Usually no user fees for NDA/BLA (must request) ■ Orphan drug grants fund some clinical research ■ May get Priority Review ○ Annual reports must be submitted if OD designation is granted

US gov't branches involved in drug regulation?

○ Executive Branch > HHS > FDA

Phase 2

○ Purpose ■ Determine if a particular agent (or combination) should be studied further ■ Serve as a critical filtering mechanism such that a negative trial would lead to discontinuation of development of the novel agent ○ Safety (Embedded in the trial to serve as stopping rule), Efficacy (Outcome variable of interest) ○ Phase IIa ■ Proof of Concept (POC) ■ Usually a 2-arm study w/ test drug given at Maximum Tolerated Dose (MTD) vs. Standard of Care (SOC) as control arm ○ Phase IIb ■ Dose finding study ■ Multiple arm study where different doses of the test compound are given vs. the standard dose of SOC

What are the Basic Generic Drug Requirements?

○ Same active ingredient(s)(inactive ingredients may vary), route of administration, dosage form, strength, indication, batch requirements for identity, strength, purity and quality ○ Manufactured under the same strict standards of FDA's GMP regulations required for innovator products ○ Inactive ingredients already approved in a separate NDA

● New Drug Application (NDA) / Therapeutic Biologic Application (BLA)

○ Submitted to FDA once all or most of the proposed studies are completed. ○ Submitted if company believes adequate positive info has been obtained to warrant a request to market the drug. ○ Contains extensive data on the investigational drug and results of the clinical trials ○ Electronic Common Technical Document(eCTD): Standard format for submitting applications (IND, NDA, ANDA, BLA), amendments, supplements, and reports to CDER and CBER. ○ CDER: application of pharmaceuticals, CBER: application for biopharmaceuticals, vaccines, blood and blood products ○ Financial Disclosure(21 CFR 54): ensure that financial interests and arrangements with Principal Investors (PIs) that could affect the reliability of data submitted to FDA in support of product marketing are identified and disclosed by the applicant (Applicable to drugs, biologics, devices) ○ Filing Review : 60 days from the receipt of the application to determine whether it is adequate for review. If inadequate, refuse to file it and sponsor can resubmit it. ○ NDA Review Clock ■ Standard NDAs: within 10 months after FDA accept filing ■ Priority application: within 6 months after FDA accept filing ■ Priority review voucher: One of ways to motivate the development of drug for therapeutic areas that people might not be developed for. ■ Major amendment can extend the review clock three months ○ Agency can request Advisory Committee meeting. ○ NDA Decision ■ Approval: Drug can be marketed in the U.S. ■ Approvable: It has problems that need to be addressed before approval. ■ Non-approvable: More significant problems that may require additional research on the drug and may require reformulation of the drug product ○ Once FDA decision is made, the review clock ends. ○ Review clock for the application resubmitted after decision: 2 ~ 6 months ○ NDA Classifications ■ New Molecular Entity (NME) ■ New Salt of Previously Approved Drug (not NME) ■ New Formulation of Previously Approved Drug ■ New Combination of Two or More Drugs ■ Already Marketed Drug Product - Duplication (i.e. new manufacturer) ■ New Indication for Already Marketed Drug, including switching from prescription to OTC ■ Already Marketed Drug Product - No Previously Approved NDA

indication

○ The use of the drug for treating a particular disease in a particular patient population. Also consider age, e.g., pediatric ○ The indication indicate: ■ Reflect the scientific evidence accurately ■ Be concisely written to include the info necessary to clearly convey the use for which the drug has been shown to be safe and effective ■ Use terminology that is clinically relevant and scientifically vaild ■ All indications listed in the label must be supported by evidence of effectiveness based on adequate and well-controlled studies.

What is Not-Regulated by FDA?

● Advertising (except Rx and medical devices) ● Alcohol ● Consumer Products ● Drugs of Abuse ● Health Insurance ● Meat and Poultry ● Pesticides ● Restaurants and Grocery Stores ● Water

Regulatory Paradox

● Aversion to uncertainty vs. Willingness to accept unknowns about a drug before approval