FDA/IP Midterm

Intended Use

-What your product does

-Answers the what it is supposed to do

Indications for Use

reasons or situations in which someone would use your product

What are some of the challenges associated with drug development?

-Drugs can take 10-15 years to develop and approve for market

-Several billion goes into development

-Generic drugs cost 80-85% less than name brand

Why might patents be helpful from an economic perspective?

-Help recover R&D costs

-Make profit for company

What does IND stand for and when is it used?

IND = Investigational New Drug (typically for clinical trials)

What is NDA in the context of drugs and when is it used?

-New Drug Application

-Used prior to manufacturing and approval launch

What is the typical drug approval process?

-Research

-Drug discovery/disease pairing

-Preclinical development (4-5 yrs)

-IND leading to clinical trials (6-9 yrs)

-NDA for manufacturing approval and launch (1-2 yrs)

How can generic drugs speed up the approval process?

They skip most of the clinical tests related to safety/effectiveness and only need to show equivalence through an Abbreviated New Drug Application or through bioequivalence of a biologic in a BLA

What was Regranex?

-Recombinant form of human platelet-derived growth factor (PDGF)

-Indications: treatment of lower extremity diabetic neuropathic ulcers with blood supply extending into subcutaneous or more

-Becplermin acts with PDGF to promote recruitment of cells to ulcer, division of cells, and formation of new skin

-Small study revealed 3+ doses linked to higher deaths from cancer in post-market surveillance (dose dependent and deaths from all cancers)

-FDA decided to weigh costs vs benefits for each patient (not recommended for patients with known malignancies)

-In June 2008, warning was added to the box about 3+ tubes, withdrawn from EU completely

-2018 → smith and nephew studies showed no increase in safety risk after 11 years; those with prior cancer had similar deaths in both groups → petition → FDA removed the warning label from boxes

-Sales peaked > $100 million prior to box warning, after warning $70-80 million

-Passed from Ethicon to Systagenix to Healthpoint to Smith and Nephew

-Regranex 360 developed in 2013 for portal/compliance

What was the Depuy ASR Acetabular System?

-Released in 2005 as metal-on-metal but vertical orientation of cup led to edge loading between cup and neck and metallosis (toxic release of metals into system from wear)

-400 complaints received regarding system since 2008

-By 2010 12-15% revision rate

-August 2010 Depuy issued a voluntary recall

-Class Action suit filed in 2011 for those implanted between 2005 and 2010 w/ 250k settlements

-call doctor, company or lawyer for those who have already rcvd it

What was the Saint Gobain Desmarquet Hip Implant Recall?

-1990s ZiO2 femoral hip balls (ceramic)

-Originally batch fired and tumble finished; sold to 7 large companies

-1998 → wanted to change firing process to decrease cost and increase revenue

-Switch from batch furnace to continuous feed furnace

-New balls passed mechanical tests but

-Balls were found to oxidize in body, losing protective coating, causing them to be unstable, wear, and fracture

-2001 global recall and meeting with ortho companies September 2001

-FDA meeting on 9/11

-9 batches of femoral heads recalled; held 85% of ZiO2 heads; expected fracture rate 8.8% within 13-32 months

-200k THR with 6% having the heads (12k)

What happened after the Saint Gobain recall?

-CeramTec made ZIO2 with toughened alumina and they predominate market (returned to top after saint gobain)

What are some important International Medical Device Standards?

-ISO13485: Medical Devices Quality Management Systems

-ISO14971 - Application of Risk Management to Medical Devices

-IEC 62366: Usability (human factors) Engineering to Medical Devices

-ISO10993: Biological Evaluation of Medical Devices

What is a medical device?

-”an instrument, apparatus, implement, machine, implant, in vitro reagent or other similar article”

-intended for use in diagnosis of disease, in cure, mitigation, treatment, or prevention of disease

-affect structure or function of body of man or animals but does not achieve primary action through chemical action or metabolism

What does an FDA quality system include?

-Design controls

-Labelling and packaging controls

-Statistical techniques

-Nonconformance standards

-Production and process control

-CAPA

-Records

-Purchasing control

-Document control

-Handling, distribution, storage and installation

Why employ QMS (good manufacturing practices)?

-Ensure products are safe and effective

-Ensure customers are happy

-Improve efficiency

-Save time/money

-Organization structure of planning, creating, verification, validation, correction, prevention

-Required under CFR and ISO13485

What is the design control process?

-Having a plan

-Determine inputs

-Determine outputs

-Design review to see if risks were mitigated

-Verification/validation

-Design and transfer changes at end of process

DHF = compilation of evidence following a specific format

What is design and development planning?

-FDA wants to see written plan of all activities in development process including things like assignment specs, risk analysis and who signs off

-Creation of living documents often in phases

-Should provide indications of who they need to interface with (who else is responsible)

-1st phase is feasibility and concept, verification and validation

2nd phase is development (requirements, reviews)

3rd-5th is how to get out door (design transfer, assigning responsibility, documentation for traceability)

What is a design input?

-Essentially a design requirement that needs to address intended use based on how you want it to be used

-Make sure requirement is unambiguous and complete or you have a way of testing it

-Should be specific, documented, and approved

-Must consider user needs, patient needs, design/development and regulations (multidisciplinary team), marketing team will understand customer

-Usually derived from research, customer requests, product issues, competitor recalls, regulations

What is risk management?

-Part of design input stage

-Goals: take as much risk out of device as possible early, continue to evaluate risk throughout product life cycle

(leave as little as possible to labeling, should be last resort)

What do product requirements/specifications typically include?

-Those directly linked to indicated and intended use

-Human factors (usability) requirements

-Safety requirements

-Regulatory requirements for ISO

-Labelling requirements

-Packaging requirements

-Sterilization requirements

-Those linked to risk mitigation with record of evaluation based on severity ranking, likelihood of occurrence, and risk level

True or False: The intended use impacts the classification of the device

True

What should an indication for use include?

-Conditions the device was designed to diagnose, treat, prevent, cure, or mitigate

-Description of target population

-Answers the who and why

What are Design Outputs?

-Allow adequate eval of conformance to design input requirements (are the input requirements satisfied?)

-Need acceptance criteria to ensure that those essential for proper function have been identified

What are some examples of design outputs?

-Risk management file

-Product drawings

-Packaging/Labeling

-Production processes

-Work instructions

-Instructions for use

What is a design review?

-meant to evaluate the ability of results of design and development to meet requirements

-like a check-up to ensure risk management is employed

-identify and propose necessary actions

-know what you have to do next to move forward

How should you conduct a design review?

-Ensure they are conducted at appropriate stages (at least one needed)

-Ensure participants included represent the design state to ask questions

-Involve outside administration for input

-Make sure it is well documented

What is design verification?

-confirmation with evidence that specific requirements have been fulfilled

-includes identification of design, methods, date and individuals performing verification as documented in DHF

-Risk management documentation should also be updated during this phase

-Risk management report should demonstrate record of potential hazard, cause of hazard, mitigation result, updated severity rating, updated likelihood of occurrence and risk level (may or may not be complete prior to next step of validation)

-Only looking at “does it meet the requirements?” less so “does it work for customer?”

What is the difference between verification and validation?

Verification: product meets requirements

Validation: product does what it is intended to do

Ex. cement life preserver → verification that all parts of life preserver are there, validation → did not act as a life preserver because person started sinking

Case Study 1: What was wrong with the laryngoscope adapter?

-Exhibited a reverse image (King Systems)

Case study 2: What was wrong with the LIFEPAK15 defibrillator?

-Failure to deliver shock after “shock” button was pressed (Stryker)

Case Study 3: What was wrong with the Exelsius GPS Flat Panel Fluoroscopy Fixture Kit?

-Calibration error leading to improper navigation leading to device misplacement (Globus)

Case Study 4: What was wrong with the BioZorb 3D Bioabsorbable Markers?

-Adverse events due to implant migrating, breaking through skin, inflammatory responses (Hologic)

-Found that they did not adequately maintain procedures to control the design of the device (deficient on design controls such as inputs, outputs, validations, translation to production, and CAPA procedures)

-Considered product misbranded because adverse events had not been reported and they failed to submit a report of corrections

What is design validation?

-Confirmation by examination of evidence that requirements of intended use are fulfilled (product functions as it says it does)

-Performed under defined operating conditions with batches/lots

-Ensures devices conform to user needs and intended uses (user knows how to use it and instructions work properly for use)

-Should be planned and include risk analysis where appropriate

What should a design validation report include?

-Intended use and ensure that device performs intended use

-Scope to application to final product

-Include test methods

-Sample size justification

-Identify product lots used

-Provide test data

-Provide results/conclusions based on statistics

-Create recommendation

What is design transfer?

-Making sure that all of the previous steps have been translated into production

-Transition into initial manufacturing where outputs products are acceptable for distribution

-Make sure they work

What is included in design transfer documentation?

-Complete device drawings

-Suppliers approved and agreements in place

-PFMEA performed

-Risk management report complete with risks mitigated

-Manufacturing procedures

-Complete procedure validation

-Equipment validated

-Trained operators

-Training validated

-Process validation complete

-First article pass inspection if necessary

What are design changes?

-Records of any changes made after verification or may be warranted after initial manufacturing of article

-Track, document and test with risk eval

-identify, document, validate, verify, review and approve prior to implementation

-When a change is made, document so you can ensure outcome/effect is tracked and documented (allows you to catch things like what would have been useful in ceramic ball recall)

Case Study 5: What was the component of implantable cardioverter defibrillator? (Emblem)

-potential for fractures which prevents device from delivering therapy (Boston Scientific)

What is a design history file?

-contains references, records and evidence necessary to demonstrate design was developed in accordance with design plan and requirements of design controls

What might a DHF include?

-Design control procedures, forms, guidance

-Executed forms that identify design control activities, design & development teams, design & development interfaces & design & development requests

-Product proposals

-Design input document and requirement matrices

-Design and manufacturing requirements

-Detailed input documents

-Design specs control matrices

-Design documents

-Design development phase/stage identification

-Design review checklists

-Design review notes/minutes

-Verification plans/checklists

-Design verification test reports

-Risk management file

-Validation test reports

-Design transfer checklist

-Design change requests

Why is a DHF important?

-If there’s a problem, you can trace it

-Makes legal situations easier to transverse through

-Have evidence in order

Why are design controls important?

-protect people from getting hurt

-recalls are expensive and competitors can use that against you

True or False: In a class I or class II recall the FDA will start going through your documents (in a DHF) to help you figure out what went wrong?

True

Case Study 6: What was wrong with the sterilization wrap/container?

-Pods for bulk sterilization had weld failures that breached the sterile barrier and led to improper sterilization of other devices (Turbett Surgical Inc.)

(they made a sterilizing bin that did not sterilize)

What does freedom to operate mean?

-A patent does not infringe on claims of other prior art

-If it does, can you do an invalidity search to knock out that patent so you can commercialize your product?

-Is it still novel and non-obvious?

-Want your features to not fall within claims of other patents

What is a FTO search?

-It’s a search to find 3rd party patents that your invention infringes (want to not find anything)

Why is it important to do an FTO search?

-Infringement can cost a lot of money if it goes to trial (millions of moolah)

-Lost sales

-Have to stop production and costs of manufacturing equipment

-It also comes back on you as the engineer if you said “sure go ahead” but you were wrong womp-womp

What are you looking for when doing an FTO search?

-Independent claims of possible infringed patents since these are the broadest claim possible

If you aren’t infringing on the broadest claim, you aren’t infringing on the dependent claims

How can you tell if your invention “reads on” from the original patent?

-Are all of the elements of the patent present in your invention → if yes, you are infringing, if no, then you are ok but it may be better just to patent the novel aspect of your invention

-Also, if no, you must also consider the novelty/non-obviousness of invention

What is literal infringement?

-Every claim is infringed on exactly as stated (all elements are described in existing patent)

-Accused device falls directly within scope of claims

What is Doctrine of Equivalents?

-Not all elements are literally described in the patent, but the added features are so minute, obvious, and seemingly less novel that they are practically the same

-Perform essentially same function, in same result, in same way

-Added details are deemed “insubstantial” (ex. the color of the bike or where the handles are placed)

-Infringement found if accused product and patented product are found to be substantially equivalent (in pharma world this is an issue)

What is licensing?

-Permission from a company to use their patent for a limited purpose

-You must put patent marking or labeling on your product if licensing so that public is aware

How does direct infringement occur?

-Without permission, you make, use, offer to sell, or sell any patented invention or import an internationally patented invention into US

-Open up to triple damages

-Paper trails/internet counts against you

How is infringement determined?

-Judge is responsible for determining the scope of claims/interpreting them (looking at how they have been described in specifications and how to interpret terminology)

-Jury decides if claimed invention has been infringed (do the claims cover the accused product)

-”You can have idiots on the jury” but there is highly educated jury pool that you want in Rochester; those elsewhere with less educated juries often work to benefit of defendant (so person who is being sued gets off easy)

How could actions taken limit the scope of your patent claims?

-If you argue in a court of law that your claim was more specific to avoid infringement, you can no longer use your broadest claim in future lawsuits

-you are bound to that narrow claim

-can’t give up something to get a patent and then reclaim it down the road

What are office actions?

-A written communication to discuss issues with patents from patent examiner including reasons for rejection

-Tend to include a time limit to respond to a rejection notice from a patent examiner

How are claims interpreted in a court of law?

1. words given ordinary/customary meaning

2. words tied into specifications and prosecution history

3. ambiguous words are defined via dictionary, test books, and experts in the field

4. limitations interpreted via sister patents (collection of patents that cover same or similar inventions)

Why was the Doctrine of Equivalence (DOE) created?

-Protects patent owner from competitors who steal essence of invention by barely avoiding the literal language of claims

-Judicially created to ensure fairness

What is the test for Doctrine of Equivalence DOE?

-Do they perform the same function?

-Do they perform this function in substantially the same way?

-Do they achieve substantially the same result?

Ex. square vs. circular bolt → same function, same way, same result of secure/fastening

If you hit all three → infringe under DOE

If you say no to one of them or there is a substantial difference → you are off the hook (not infringing)

What are the limitations to a DOE?

-Prosecution History Estoppel (PAIR) → if you gave up claim specificity or changed claims to avoid lawsuit previously that narrowed them, you cannot use broader/original claims. This prevents patent owner from extending range of coverage by resurrecting subject matter given up during prosecution to get patent (no take-backsies)

-Prior art: if asserted scope of equivalents “reads on” prior art (ie. now your expansion reads on different prior art or same prior art because it’s now too broad)

What do you have to send back as a response if you get rejected but want to continue with patent?

-Description of each and every relevant patent you found and whether or not you have infringed the patent (long document)

Why is it important to know how to draft claims?

-As the inventor, you will do the first round of claim drafting

-Your patent attorney then massages the wording into appropriate patent style/language

What can you not claim in a claim?

-A result

-A function or functional language (what it does)

What questions must you answer prior to claim drafting?

-What the invention is

-What the parts and components that make up the invention are

-How the pieces/parts connect to one another

-If you have more than one invention

-If there are multiple versions of each invention

How to draft patent claims

-Start with broad statement of invention (no function)

-Use transitional language like “comprising”

-Introduce the elements and how they connect to one another (coupled to, mounted to, fixed to etc.)

-Make sure independent claims are broad, with dependent claims narrowing scope sequentially

What can you patent?

-Article of manufacture

-Composition of matter

-Method

-Machine

-Can only patent one thing at a time (can’t do surgical device and method in same patent)

How many claims are you allowed to have?

In the U.S. you are allowed 20 claims in total but there is an additional charge to add more

What is DABT?

American Board of Toxicology, Diplomate meaning a board certification of toxicologists

What are the biological risks associated with using a medical device?

For those that come into direct or indirect contact with the body, this includes:

-chemical toxicity

-unacceptable biological response to physical characteristics of device

-aspects of manufacturing that could alter the physiochemical characteristics of the device leading to changes in biocompatibility response

To be considered biocompatible, what must the device not do?

-Should not produce adverse local or systemic effects

Local effects = cytotoxicity, skin irritation, skin sensitization, implantation effects, and material-mediated pyrogenicity (fever)

Systemic effects = acute/subchronic/chronic toxicity, genotoxicity, hemocompatibility, carcinogenicity, and reproductive toxicity

To determine, systematic testing is required

What ISO standard is responsible for aspects related to biocompatibility?

ISO10993 - Biological evaluation of medical devices

What do the ISO10993 guidelines cover?

-Biological evaluation/testing

-Animal welfare

-Genotoxicity, carcinogenicity, reproductive toxicology

-Interactions with blood

-Cytotoxicity

-Implantaion

-ETO sterilization residuals

-Degradation products

-Skin sensitization

-Systemic toxicity

-Sample prep/reference materials

-Degradation of polymeric devices

-Degradation of ceramic devices

-Degradation of metals and alloys

-Toxicokinetic study design

-Toxicological risk assessment

-Chemical characterization

-Physico-chemical, morphological & topographical characterization of materials

-Immunotoxicity testing

-Nanomaterials

-Tests for irritation

When is biocompatibility testing needed?

-standard pre-market non-clinical testing for a new device

-modification to an existing device (change in material vendor, coating, colorant, sterilization, manufacturing process, manufacturing site)

-Attachment D for flowchart determines what is needed in the guidance document of biological evaluation of medical devices w/ risk-based approach

What are some exceptions to biocompatibility testing?

-The FDA does not clear or approve individual materials used in fabrication of medical devices

-Risk assessment should evaluate materials as well as processing, manufacturing and residuals → TESTING SHOULD BE PERFORMED ON FINAL, FINISHED MEDICAL DEVICES

What is the FDA Biocompatibility Resource Center?

-Educates medical device manufacturers

-Outlines steps along with links for further info/downloadable materials

-Tells you what to put in a test report

What biocompatibility evaluations are needed?

-Depends on nature of body of contact (surface, externally communicating, or is it an implant?)

-What is the degree/type of contact? (intact skin, breached skin, mucosal membrane, blood path, tissue/bone)

-What is the duration of contact? (limited less than or equal to 24 hours, prolonged is greater than 24 hours but less than 30 days, permanent is greater than 30 days)

-FDA wants worst case = total amount of time before replacement

Biocompatibility Case study 1: Hip Implant

-Tissue/bone

-Permanent

-Cytotox, sensitization, irritation, acute systemic toxicity, material-mediated pyrogenicity, subacute toxicity, genotox, implantation, chronic tox, carcinogenicity

Biocompatibility Case Study 2: Electric toothbrush

-Surface device, mucosal membrane, prolonged

-Cytotox,sensitization, irritation, acute systemic tox, pyrogenicity (maybe but could provide justification), subchronic toxicity, implantation

How are risks and benefits assessed in terms of biocompatibility?

-Weighing risks depend on population and severity

-If the device doesn’t have to do with life-saving care, fewer tests are likely to be required and there are less risks to outweigh benefits

-No one wants to do a 2-year carcinogenicity study if they do not have to

What are some exceptions to the biocompatibility guidance?

-2023 guidance says that all biological effects in matrix may not be relevant for all devices

-Scientific rationale should be used to support use of previous data or to justify why a biocompatibility test was not performed

-Chemical formulation and processing info can assist sponsor to support justifications for waiving testing for recommended endpoints (tell them what the constituents and processing effects are as justification; remember, must be in reference to end product)

Cytotoxicity

-Cell damage or death caused by device either via direct contact or extractable/leachable substances

-Cell culture medium elution method → extracts of device added to cells (most common)

-Direct contact of device materials with cells (used only with novel device materials)

Irritation

-Likelihood of device to cause inflammatory response to single, repeated, or continuous application of a material

-Often conducted in rabbits topically or injected into skin (intracutaneous reactivity)

-Should match route and duration of exposure/contact for clinical use (skin, mucous membrane, eye)

Skin Sensitization

-Determines likelihood of device to induce delayed hypersensitivity allergic response in skin

-Mouse local lymph node assay, guinea pig maximization test, Beuhler test for guinea pig topical devices

Systemic Toxicity

-Acute (single-exposure injection), less than 24 hours (rodents) with extracts and animals observed at least 3 days after exposure

-Subacute/subchronic (14-90 days of repeated exposure) includes systemic toxicity endpoints such as blood cells/proteins, organ weights, histopathological examinations

-Chronic (6 months to 2 yrs exposure) represents long-term to lifetime exposure similar to subchronic but more time points (interim and terminal sacrifices) with more animals per group

Genotoxicity

-Determine potential of test material (device extract) to induce genetic damage

Both in vitro and in vivo assays (ames baterial mutagensis, mouse lymphoma, mammalian cell chromosomal aberration, mouse micronucleus)

How are extracts obtained?

-Soaking implant in polar (saline) and non-polar (sesame oil) extracts

-Incubated 24-72 hours at 37 degrees celsius

Implantation Testing

-Evaluates local effects from implantation such as inflammation, tissue necrosis, fibrosis, vascularization

-For both long-term and short-term implanted devices

-Variety of animal models accepted

-Requires histopathology of local tissue and the explanted device after certain periods of implantation

-ISO 10993- specifies testing in subcutaneous tissue, muscle and bone because clinically appropriate implantation sites may be necessary

Carcinogenicity

-Evaluates tumorigenic potential of device

-Can be combined with chronic systemic toxicity study

-Often not performed because time consuming and expensive and not required if risk can be assessed through literature or chemical means

Reproductive Toxicity

-Evaluates potential of device to impact reproductive function and/or developmental impacts on offspring (continued exposure during gestation or in utero exposure)

-Conducted in rodents and rabbits

-Often not performed (not required it risk can be assessed through literature/chemical means)

What is chemical characterization testing?

-Identification and semi-quantitation of extractable and leachable substances of a device

-capture materials of construction such as polymers, monomers, degradation products, metallic ions, chemical constituents

-Look for residual chemicals in manufacturing process

-could be done through mass spectrometry and other molecular techniques

Extractables and Leachables

-Extractables - substances released under exaggerated conditions (high temps around 50-70 degrees Celsius, solvents of different polarity like hexanes, isopropanol and water)

-Leachables migrate from contact surfaces under normal conditions for storage and use → often 37 degrees Celsius using saline and simulated sweat or blood (imitate biological conditions)

When to use extractables or leachables?

Leachables are subset of extractables meaning that when you want to capture most or all of chemical constituents, opt for extractables

How is estimated exposure dose calculated?

-Guidance 10993 Toxicological risk assessment

-Use characterization data from extractables quantified (through mass spec) to estimate exposure dose

How is margin of safety (MOS) calculated?

-Tolerable intake derived from scientific literature

-MOS calculated for each constituent included in toxicological risk assessment

-MOS = Tolerable Intake (from lit)/Estimated Exposure Does (EED) from mass spec

-MOS > 1.0 is acceptable risk and can waive certain longer-term systemic toxicity testing

Biocompatible Case Study 3: Orthopedic Implants

-8 different sets of materials

-Wanted 510k for change in manufacturing which would require large amount of testing

-Tried to use chemical characterization approach to waive longer-term testing

-Compared extractables of test devices with their predicate control to establish toxicological equivalence

-Determined no additional risk

-Also can get around this by testing worst case scenario (let’s say one implant had the worst known material, test that one)

Biocompatibility Case Study 4: Evaluation of Wearable Electronic

---

-No previous experience with FDA

-Conducted gap analysis based on prior testing and materials of construction but no animal testing policy and need skin/irritation testing

-Did in vitro teting for cytotoxicity and leachables for irritants/sensitizers

-Leveraged data from testing and literature to provide justification for no animal testing

Interaction Avenues with FDA

-Pre-subs can ask questions about expectations for testing prior to conducting biocompatibility evaluation

-Post-sub feedback with comments on conformance to test standards, opportunity to respond/clarify/provide justification for deficiencies, like a journal review process

Case Study 5: refuse to accept

-Propose biocompatibility testing for external communicating device, feedback was that there would need to be more testing, company pushed back

-Submitted application and received Refuse to Accept” from FDA because not enough biocompatibility testing

Lesson: complete the testing requested by FDA and start early (they are still doing biocompatibility testing 2.5 years later)

Case Study 6: outdated standard deficiency

-Tests performed regarding chemical characterization with guidance from 2019 when study was completed, new guidance updated January 2020

-FDA wanted test to be repeated entirely

-Approached the deficiencies one at a time to see if data was still applicable

-Managed to use literature and additional evaluation of manufacturing process contact materials to get out of longer term genotoxic/carcinogenic studies

-Cleared via 510(k)

Result: Leverage existing data and sometimes conduct few extra short tests