# Presentation: 222866

## Regulatory Considerations in Drug and Device Development:The Process and the Science 

**John H. Powers, MD**
***Lead Medical Officer***
***Antimicrobial Drug Development and Resistance Initiatives***
***Office of Drug Evaluation IV***
***Center for Drug Evaluation and Research***
***U.S. Food and Drug Administration***

## Introduction

**Background on U.S. Food and Drug Administration (FDA)**
**mission, goals, and short history**
**current structure of FDA**
**Process of drug development**
**definitions of common terms**
**phases of drug development**
**Process of device development**

## The Basis of Science and Regulation

**Science is a social endeavor**
**As a social endeavor, science must follow a set of standards to have meaning**
**Investigators must use standardized definitions and a common set of standards of evidence**
**Regulation is the standardization of a level of evidence that is scientifically and ethically acceptable to promote and advance public health**

## The Scientific Method

**Roger Bacon, monk, philosopher and alchemist**
**Described scientific method in 13****th**** century**
**Repeating cycle of:**
**Observation**
**Hypothesis**
**Experimentation**
**Verification/replication**
**Regulations are based on GOOD SCIENCE**
**Not “hurdles”**
**Not “just for licensing”**

## The Basis of Science and Regulation

**Confusing “might” with “right”:**
**Regulations should not be a set of arbitrary rules set in place “just because” to impede access to drugs (“might”) – focus on what you “can’t” do**
**Regulations should be  based upon appropriate scientific standards to ensure an adequate degree of certainty in effectiveness and safety for patients ( doing what’s “right”) –  focus on what you “can” do**
**Regulations provide benefit  to: **
**to patients by ensuring a common level of certainty **
**to sponsors by providing common set of standards that they need to reach to obtain licensing approval**

## The Basis of Science and Regulation

**Randomized controlled trials are gold standard for determining causal relationship between medical interventions and outcomes**
**Trials begin with “null hypothesis” that intervention is NOT safe and effective and accumulate evidence to determine if this is unlikely to be true**
**Not denying “life saving” therapies if one has not evaluated evidence as to whether they are life saving or not**
**Medical need is reason to evaluate an new intervention, not evidence it is effective**

## Mission and Goals

**The Food and Drug Administration Modernization Act (FDAMA) of 1997 affirmed FDA’s public health protection role and defined the Agency’s mission: **
**“****to promote public health by promptly and efficiently reviewing clinical research and taking appropriate action on the marketing of regulated products in a timely manner.****”**

## Background

**U.S. Food and Drug Administration regulates a wide range of products including foods, cosmetics, drugs and medical devices**
**FDA regulated products make up 1 trillion dollars worth of products and account for 25% of consumer spending**
**FDA has approximately 10,000 employees**
**FDA  HQ located in Washington, DC, and across DC suburbs**

## Background

**Regulatory authority comes from Food, Drugs and Cosmetic (FD&C) Act enacted in 1938 after tragedy with Elixir of Sulfanilamide**
**Code of Federal Regulations (CFR) is interpretation of FD&C Act**** **
**Original act specified drug sponsor only had to demonstrate safety of drug product**
**Kefauver-Harris Amendments  in 1962 specified that drug product must be effective as well as safe after issues with thalidomide**
**Medical device regulations enacted in 1976**
**FDA determines safety and effectiveness of products**

## Background

**Executive branch of government**
**Department of Health and Human Services (DHHS)**
**U.S. Food and Drug Administration (FDA)**
**Center for Biologics Evaluation and Research**
**Center for Devices and Radiological Health**
**Center for Food Safety and Applied Nutrition**
**Center for Veterinary Medicine**
**National Center for Toxicological Research**
**Center for Drug Evaluation and Research (CDER)**
**Office of New Drugs (OND)**
**Office of Surveillance and Epidemiology (OSE)**

## Regulation of Drugs

## Background

**CDER mission to oversee research, development, manufacture, and marketing of drugs.**
**Review clinical trial evidence of safety and effectiveness of new drugs before approving them for marketing**
**Monitors drugs post-marketing performance for health risks **
**Ensures that drug labeling, drug information for patients, and drug promotion are truthful, helpful, and not misleading**

## Background

**Each drug reviewed by a multi-disciplinary team**
**Project Manager/Consumer Safety Officer**
**coordinates team**
**point of contact for drug sponsors**
**Biopharmacologists**
**Chemists**
**Clinicians**
**Microbiologists**
**Pharmacology/toxicologists**
**Statisticians**
**Review of primary data, validity of data, chemistry**

## Drug Development ProcessDefinitions

**Drug**** - any substance used to diagnose, cure, mitigate, treat or prevent a disease (FD&C Act)**
**Disease**** defined in the dictionary as “a condition that results in medically significant symptoms”**
**Effectiveness**** -  impact of drug on outcomes clinically relevant to patients, such as how a patient *****feels, functions, or survives***
**Direct measurement of clinical endpoints**
**Surrogate endpoints proven to predict clinical outcomes**
**Safety**** – all drugs associated with some harms**
**all tests reasonably applicable to evaluate**
**describing the adverse events associated with administration of drug**

## Drug Development ProcessDefinitions

**Effectiveness**
**Requirement for “substantial evidence” from “adequate and well controlled trials” since 1962**
**trials of adequate size and design to determine a difference should such a difference exist**
**uncontrolled trials are usually not acceptable**
**testing a hypothesis in a clinical trial, such as “drug X is superior to drug Y by Z%”**

## Adequate and Well-Controlled

**Clear statement of objectives of trial**
**Study design permits valid quantitative comparison with a control**
**Select patients with disease (treatment) or at risk of disease (prevention)**
**Baseline comparability (randomization)**
**Minimize bias (blinding, etc.)**
**Appropriate methods of assessment of outcome with well defined and reliable endpoint**
**Appropriate methods of analysis**
**21 CFR 314.126**

## Drug Development ProcessDefinitions

**Safety**
**no drug is completely safe**
**implies concept of risks of adverse effects compared to benefits of receiving drug**
**takes into account seriousness of disease and available alternative therapies and seriousness and frequency of adverse effects**

## Drug Development ProcessDefinitions

**Safety**
**usually NOT testing a hypothesis but providing descriptive statistics only**
**sample size of clinical trial database often too small to determine rare events**
**“****Rule of three” - no events in a given sample rules out a risk of denominator divided by three**
**e.g. no events in 3000 patients rules out risk of 1:1000 (compare to risk of hepatotoxicity in general population of 1:1,000,000)**

## Drug Development Process Definitions

**Safety**
**Important to look at absolute number of patients potentially experiencing adverse event as well as relative risk**
**risk of visual abnormalities:**
**voriconazole 30% of 5000 patients with invasive aspergillosis is 1500 patients and few available therapies**
**Safety and effectiveness considered as separate units of analysis (need effectiveness first to justify adverse events) but need one integrated decision on overall risk-benefit**

## Drug Development Process

## Drug Development ProcessOverall Development Plan

**Overall goal to gather evidence that drug is safe and effective in treatment and/or prevention of diseases under study under conditions of use**
**Decide which indications to pursue and whether drug is to treat or prevent disease**
** **
**Speak with relevant Division at FDA about overall development plan and number of studies required for approval**

## Development ProcessPhases of Drug Development

**Pre-clinical data**
***in vitro***** data showing biological activity**
**carcinogenicity  **
**animal toxicology (NOAEL) by going to high enough dose to observe some effect**
**Phase 1**
**first introduction of investigational new drug in humans usually performed in healthy volunteers**
**used to determine absorption, metabolism, distribution, elimination in humans**

## Development ProcessPhases of Drug Development

**Phase 2**
**early controlled clinical trials, dose response**
**preliminary efficacy of drug in patients**
**determine common short term side effects**
**Phase 3**
**pivotal information on safety and efficacy**
**further information on dose**
**adequate and well -controlled trials**
**basis for extrapolating results to general population and product labeling**
**Phase 4**** - post-marketing**

## Drug Development Process

**Investigational New Drug (IND)**** Application**
**needed whenever a sponsor wishes to study a new drug or an approved drug at a new dose, new route of administration in a new population**
**houses all data prior to submission of NDA**
**New Drug Application (NDA)**
**information from IND as well as Phase 3 trials submitted for application to market a drug**

## Drug Development Process

## Drug Development Process

**Fast Track Designation**
**products for serious and life threatening diseases**
**products that have potential to address unmet medical need**
**sponsor can request at time of submission of IND or any time thereafter prior to approval**
**schedule of meeting and written correspondence**
**eligibility for priority review or accelerated approval**

## Drug Development Process

**Accelerated Approval (two forms)**
**serious and life threatening diseases without good alternative therapies**
**approval based on surrogate endpoints reasonably likely to predict clinical benefit**
**contingent on follow-up studies to confirm therapeutic benefits to patients**
**restricted distribution**
**Priority review**
**products with significant improvement in safety or effectiveness**
**not limited to serious and life threatening diseases**

## Regulation of Devices

## CDRH Organization

**FDA**

**CDRH**

- CBER

- CFSAN

- CDER

- CVM

- OST

- OHIP

- OSB

- OSM

- OIVD

**ODE**

- DAGID

- DOED

- DRARD

- DGRND

- DCD

## Office of Device Evaluation	

- Office of Device Evaluation

**OFFICE OF THE DIRECTOR**

**Division of Reproductive, Abdominal, ENT & Radiological Devices**

**Division of Ophthalmic Devices**

**Division of General, Restorative & Neurological Devices**

**Division of Anesthesiology, General Hospital, Infection Control, and Dental Devices**

**Division of Cardiovascular Devices**

**Notes:**
The Office of Device Evaluation is responsible for the premarket review of medical devices. 
 There are currently five divisions divided by medical specialty area.  
Other offices in the Center for Devices and Radiological Health include the Office of Compliance which is responsible for assuring regulatory compliance, the Office of Surveillance and Biometrics which is responsible for postmarket surveillance and the Office of Science and Technology which provides laboratory support and standards development.  

## Device Regulations

**FD&C Act (21 U.S.C 301 et seq.)**
**Device Defined in Sec 201(h): **
**Intended to diagnose, cure, mitigate, treat, or prevent a disease or condition; **
_**or**_
**Affects the function or structure of the body;**
**	**_**and**_
**Does not achieve intended use through chemical action in/on body; and is not metabolized to achieve purpose**

**Notes:**
FDA’s authority to regulate devices is through the Federal Food Drug and Cosmetic Act.

The term device is defined in Section 201 H and includes any product intended to treat or diagnose a disease or condition or affect body function. And the last bullet differentiates devices from drugs in that devices are not metabolized in the body to achieve their intended purpose.

## CDRH Specifics

**Medical Device Amendments of 1976 to the Federal Food, Drug, and Cosmetic Act**
**21 CFR Part 800:  Medical Devices**
**21 CFR Part 900: Mammography**
**21 CFR Part 1000: Radiological Health**

## Risk-Based Classification

**Class I: simple, low risk devices**
- General controls
- Most exempt from pre-market
-     submission
**Class II: more complex, higher risk**
- Performance standards
- Pre-market Notification[510(k)]
**Class III: most complex, highest risk**
- Clinical data needed
- Pre-market Application [PMA]

**SURGICAL GLOVES**

**INFUSION PUMPS**

**HEART VALVES**

## Center for Devices and Radiological Health Pre-Marketing Review

** ****Devices divided into Classes for purposes of review**
** ****For Class III Devices:**** **
**Premarket Approval Application (PMA) similar to NDA for new drugs**
**Requires clinical trials**
** ****For Class I, II and a few Class III Devices (for which a predicate device exists):**
**Premarket Notification (510k)**** **
**Comparison to previously approved device****	**

**Notes:**
There are basically two types of applications for marketing clearance of new medical devices.
There is the PMA process for new technology devices where predicate devices do not exist.  Examples include heart valves, pacemakers, coronary stents, endovascular grafts just to name a few.

The PMA process provides details concerning the device materials, testing, and processing.

The other process to market clearance is referred to as the premarket notification process or 510K.  It provides for a comparative information between the new device and predicate device.  Details on the comparative testing and modifications to the predicate are provided in this submission.  

## FDA APPROVES / DISAPPROVES MARKETING CLEARANCE FOR FINISHED PRODUCTS (DRUGS, DEVICES, BIOLOGICS)

**not technologies**
**not materials**
**not processing techniques**
**not additives **

**Notes:**
FDA reviews and clears products, NOT materials, NOT Technologies, and NOT Processing techniques.

## CDRH Regulations: Safety and Effectiveness

**21 CFR 860.7**
**...****.”reasonable assurance that the device is safe and effective for its conditions of use.”**
**Effectiveness is based on valid scientific evidence.**
**“...****.shall consist principally of well-controlled investigations.”**
**Examples cited as control groups: No treatments, Placebo control, Active treatment control, Historical control.**

**Notes:**
Substantial evidence of safety and efficacy  (CDER and CBER) vs. reasonable assurance of safety and effectiveness (CDRH)

## Key Differences from Drugs 

**Generally no need for Phase II (dose-finding studies).**
**Generally no regulatory requirement for a “confirmatory” clinical trial**

## Combination Product

**Combination Product (21 CFR 3.2(e)):**
**a product comprised of two or more regulated components that are physically, chemically or otherwise combined or mixed as a single entity;**
**two or more separate products packaged together (e.g., drug and device products); or**
**provided separately but intended for use together where both are required to achieve the intended use, indication, or effect and where mutually conforming labeling is needed.**

## Office of Combination Products (Established December 24, 2002)

**Assignment of combination products to “lead center” based on primary mode of action**
**Inter-center consultation/collaboration**
**Ensure timely and effective premarket review **
**Consistent and appropriate postmarket regulation**
**Dispute resolution (timeliness vs. substance)**
**Review/update guidance, agreements, practices**

- P. L. 107-250 -- enacted 10-26-02

## Examples: Antimicrobial Agents in Cleared / Approved Devices

**silver, silver cpds**
**chlorhexidine cpds**
**triclosan**
**nitrofurazone**
**bacitracin zinc**
**minocycline**
**polymyxin B sulfate**

**rifampin**
**methylene blue**
**crystal violet**
**dicloxicillin**
**combinations of these**

**Notes:**
This list shows some examples of the types of antimicrobial agents included in devices that have been cleared or approved. 

## Examples: Device TypesCleared / Approved

**catheters - intravascular, urological, peritoneal, etc.**
**wound care products - dressings, etc.**
**dental - toothbrush, floss, instrument covers**
**implanted devices - surgical mesh, orthopedic fixation, ear tube, heart valve**

**Notes:**
FDA has been receiving an increasing number of submissions and inquiries on antimicrobial agents used in devices. The list shows the wide variety of device types that have been cleared or approved.

## Contact Information – Office of Combination Products

**Mark D. Kramer**
**Director, Office of Combination Products **
**15800 Crabbs Branch Way (HFG-3)**
**Rockville, MD 20855**
**(301) 827-9229**
_**combination@fda.gov**_
_**http://www.fda.gov/oc/combination/default.htm**_

## Contact Information for Devices

**Bob Gatling**
**Program Operations**
**Center for Devices and Radiological Health **
**9200 Corporate Boulevard (HFZ-450)**
**Rockville, MD 20850**
**(301) 594-3055**

## Product Development Process

**“****Critical Path” Initiative**
**released by FDA in 2004**
**goal to find better tools to streamline drug development process**
**better predict safety and efficacy of products**
**FDA can provide guidance on what tools may be most helpful**
**www.fda.gov/oc/initiatives/criticalpath**

## Conclusions

**Communication is one of keys to drug development process**
**Take advantage of opportunities to discuss options with FDA**
**“****Failing to plan is planning to fail”**
**Develop future tools during current trials**