DRUG DEVELOPMENTDRUG DEVELOPMENTAND REGULATIONAND REGULATION

Joseph Hanig, Ph.D.Joseph Hanig, Ph.D.

Historical BackgroundHistorical BackgroundWhy were Laws Needed?Why were Laws Needed?

• Adulteration for economic gainAdulteration for economic gain• Early English Law - King John promulgates Early English Law - King John promulgates

rules on contamination of flour – Assizes of rules on contamination of flour – Assizes of BreadBread

• Quack medicines, hidden ingredients, Quack medicines, hidden ingredients, misbranding in early Americamisbranding in early America

• American meat products rejected by EuropeAmerican meat products rejected by Europe• Publication of Publication of The Jungle The Jungle by Upton Sinclairby Upton Sinclair• Tetanus contaminated diphtheria vaccineTetanus contaminated diphtheria vaccine

Virus  Toxin Act of 1902Virus  Toxin Act of 1902

• premarket clearance for safety and premarket clearance for safety and efficacy efficacy

• factory inspection factory inspection

• batch certification batch certification

Food and Drug Act of l906 Food and Drug Act of l906 (Wiley or Heyburn Act)(Wiley or Heyburn Act)

• first main federal drug lawfirst main federal drug law

• targeted adulteration and misbranding targeted adulteration and misbranding

• established the U.S. Pharmacopeia and established the U.S. Pharmacopeia and National Formulary to establish and National Formulary to establish and regulate reference standards regulate reference standards

The Sherley Amendment of The Sherley Amendment of l912l912

• prohibited use of fraudulent prohibited use of fraudulent therapeutic claims therapeutic claims

• placed burden of proof on placed burden of proof on government and resulted in weak or government and resulted in weak or non-enforcement due to the paucity non-enforcement due to the paucity of modern scientific techniques and of modern scientific techniques and tools tools

The Food, Drug and The Food, Drug and Cosmetic Act of l938 Cosmetic Act of l938

(Copeland Act)(Copeland Act) • premarket clearance for safety only premarket clearance for safety only

• factory inspection institutedfactory inspection instituted

• drug could become approved if FDA drug could become approved if FDA did not act within a specified did not act within a specified deadline deadline

The Federal Insecticide, The Federal Insecticide, Fungicide and Rodenticide Fungicide and Rodenticide

Act (FIFRA) Act – l947Act (FIFRA) Act – l947

• defined the LD-50 defined the LD-50

• established classes of toxicity based on established classes of toxicity based on order of magnitude of dose producing an order of magnitude of dose producing an LD-50 LD-50

• require a label to be written for a pesticide require a label to be written for a pesticide as well as registration with USDA as well as registration with USDA

The Durham Humphrey The Durham Humphrey Amendment of l951Amendment of l951

• defined the modern practice of pharmacy defined the modern practice of pharmacy

• established pharmacist - physician relationshipestablished pharmacist - physician relationship • established a separate class for narcotics and established a separate class for narcotics and

physician registration numbers physician registration numbers

• deals with "Legend Drugs" – drugs which bear deals with "Legend Drugs" – drugs which bear the warning "Caution Federal Law Prohibits the warning "Caution Federal Law Prohibits Dispensing Without Prescription" e.g. Rx drug Dispensing Without Prescription" e.g. Rx drug

Insulin and Antibiotic Insulin and Antibiotic Certification Amendments Certification Amendments

’41, ’43, ’45, ’49, ’52’41, ’43, ’45, ’49, ’52

• required batch certification of all required batch certification of all Master Lots (bulk product) as well as Master Lots (bulk product) as well as all lots of finished product all lots of finished product

• required batch certification of all lots required batch certification of all lots of antibiotics before they could be of antibiotics before they could be sold sold

The Kefauver – Harris Act of The Kefauver – Harris Act of l962l962

• premarket clearance for safety and efficacy premarket clearance for safety and efficacy

• establishment of "Investigational Exemption for a New establishment of "Investigational Exemption for a New Drug (IND) which required animal data to be submitted Drug (IND) which required animal data to be submitted and evaluated before clinical trial could begin and evaluated before clinical trial could begin

• established 3 phases of clinical testing established 3 phases of clinical testing

• made approval or denial of an NDA an FDA requirement made approval or denial of an NDA an FDA requirement rather than the default approval of the 1938 law rather than the default approval of the 1938 law

• established modern drug review and approval procedures established modern drug review and approval procedures

DESI Evaluation of l966; DESI Evaluation of l966; completed l969-70completed l969-70

Established panels that rated pre 1966 Established panels that rated pre 1966

drugs as: effective; probably drugs as: effective; probably effective; possibly effective and effective; possibly effective and

ineffective and drove the last two ineffective and drove the last two categories off the market unless new categories off the market unless new

evidence was presented evidence was presented

Comprehensive Drug Abuse Comprehensive Drug Abuse Prevention and Control Act Prevention and Control Act

of 1970of 1970 • Established the DEA in the Dept of Justice Established the DEA in the Dept of Justice

• Established 5 schedules for drugs of abuseEstablished 5 schedules for drugs of abuse

• Established penalties for misuse Established penalties for misuse

• Established quotas for manufacturing of Established quotas for manufacturing of narcotics narcotics

Important Legislative Important Legislative Developments of the 70’sDevelopments of the 70’s

• Over-the-Counter (OTC) Evaluation Over-the-Counter (OTC) Evaluation Monographs l972 – present Monographs l972 – present

• Supreme Court Ruling of 1973 concerning the Supreme Court Ruling of 1973 concerning the authority of FDA authority of FDA

• Drug Listing Act of l972 Drug Listing Act of l972

• Good Laboratory Practices regulations; Good Laboratory Practices regulations; proposed 1976; finalized l979 proposed 1976; finalized l979

Orphan Drug Act of 1983Orphan Drug Act of 1983

• defined orphan drugs defined orphan drugs

• encouraged their manufacture by encouraged their manufacture by giving companies exclusivity and tax giving companies exclusivity and tax relief relief

Drug Price Competition and Drug Price Competition and Patent Term Restoration Patent Term Restoration

Act – 1984Act – 1984 • established the "so called" generic drug established the "so called" generic drug

• established the concept of bioequivalence for established the concept of bioequivalence for generic drugs (generic drugs (+ + 20% of the rate and extent of 20% of the rate and extent of absorption of the innovator drug and the generic is absorption of the innovator drug and the generic is considered to be equivalent to the innovator brand) considered to be equivalent to the innovator brand)

• established the abbreviated NDA called ANDA that established the abbreviated NDA called ANDA that did not require a repeat of safety and efficacy did not require a repeat of safety and efficacy studies of the innovators, just bioequivalency studies of the innovators, just bioequivalency studies studies

Generic Drugs Act – 1990Generic Drugs Act – 1990

• established criteria and standards for established criteria and standards for generic drug manufacture generic drug manufacture

• established the FDA Office of generic established the FDA Office of generic drugs to oversee the law and drugs to oversee the law and administer the approval process administer the approval process

Prescription Drug User Fee Prescription Drug User Fee Act (PDUFA) of l994; l997; Act (PDUFA) of l994; l997;

2000; 20032000; 2003

• industry provides FDA funds in the industry provides FDA funds in the form of fees to pay for positions and form of fees to pay for positions and resources to review new drug resources to review new drug application application

• review time speeded up and drug lag review time speeded up and drug lag shortened shortened

FDA Modernization Act - FDA Modernization Act - l997l997

• abolishes insulin certificationabolishes insulin certification

• abolishes antibiotic monographs abolishes antibiotic monographs

Pediatric Exclusivity Act of Pediatric Exclusivity Act of 19981998

• Provides for FDA to request non-Provides for FDA to request non-manditory research studies on drugs manditory research studies on drugs with toxicity issues that are used in with toxicity issues that are used in childrenchildren

• Provides exclusivity or drug patent Provides exclusivity or drug patent extension for those companies willing extension for those companies willing to perform these voluntary studiesto perform these voluntary studies

Drug Development - Drug Development - Methods used to identify Methods used to identify compounds with potential compounds with potential

therapeutic usefulnesstherapeutic usefulness • Screening – most new drugs discovered this Screening – most new drugs discovered this

way way • screen is a specified set of procedures to screen is a specified set of procedures to

which a series of compounds is subjected to which a series of compounds is subjected to both both in vivo in vivo and and in vitro in vitro

• quantitative part of screening is the quantitative part of screening is the bioassay bioassay

• bioassay used to establish relationship bioassay used to establish relationship between dose and response and compare between dose and response and compare unknowns to standards unknowns to standards

Synthesis, Purification & Synthesis, Purification & Data MiningData Mining

• Synthesis of drug Synthesis of drug de novode novo

• Modification of structure of existing Modification of structure of existing drugs – structure – activity studies (SAR) drugs – structure – activity studies (SAR)

• Purification of drugs from natural sources Purification of drugs from natural sources such as native, folklore or herbal such as native, folklore or herbal medicines medicines

• Exploration of side effects of existing Exploration of side effects of existing drugs - awareness of potential usefulness drugs - awareness of potential usefulness of side effectsof side effects

Animal Studies - Preclinical Animal Studies - Preclinical StudiesStudies

Acute toxicity tests Acute toxicity tests • one administration of chemical to each one administration of chemical to each

animal animal

• generation of dose – response curves generation of dose – response curves

• Appropriate pharmacological testing to Appropriate pharmacological testing to determine ED50 determine ED50

• Develop analytical methods for Develop analytical methods for determining absorption, excretion, determining absorption, excretion, distribution and metabolism of chemical distribution and metabolism of chemical

Animal Studies - Preclinical Animal Studies - Preclinical Studies Studies

– Subchronic toxicity tests Subchronic toxicity tests

• usually 60 –90 days duration usually 60 –90 days duration

• multiple administrations or multiple administrations or continuous exposure via food or continuous exposure via food or water to one dose level of a chemical water to one dose level of a chemical per animal per animal

Animal Studies - Preclinical Animal Studies - Preclinical StudiesStudies

• Chronic toxicity tests Chronic toxicity tests

– 2 to 5 years duration depending on 2 to 5 years duration depending on species species

– multiple administrations or multiple administrations or continuous exposure via food or continuous exposure via food or water to one dose level of a water to one dose level of a chemical per animal chemical per animal

Clinical StudiesClinical Studies

– Notice of Claimed Investigational Notice of Claimed Investigational Exception for a New Drug (IND) Exception for a New Drug (IND)

– Phase I of clinical studies Phase I of clinical studies – pharmacological investigation pharmacological investigation – one or two clinical pharmacologists one or two clinical pharmacologists – healthy volunteers – informed consent healthy volunteers – informed consent

– one tenth of dose for PK studies – one tenth of dose for PK studies

Clinical Studies Clinical Studies (continued)(continued)

Phase II of clinical studiesPhase II of clinical studies

– initial controlled clinical evaluation initial controlled clinical evaluation – more than two clinical pharmacologists more than two clinical pharmacologists – selected volunteer patients with selected volunteer patients with

specific disease indication for drug specific disease indication for drug – double blind studies double blind studies

Clinical Studies Clinical Studies (continued)(continued)

Phase III of clinical studiesPhase III of clinical studies

– extended clinical evaluation extended clinical evaluation – usually 50 – 100 clinicians usually 50 – 100 clinicians – usually 500 – 1000 patients usually 500 – 1000 patients

8

DEFINITION OF A NEW DRUGDEFINITION OF A NEW DRUG • Any chemical or substance not previously used Any chemical or substance not previously used

in humans for the treatment of a disease in humans for the treatment of a disease • Combinations of approved drugs or of old drugs Combinations of approved drugs or of old drugs

even though the individual components are not even though the individual components are not new drugs new drugs

• An approved drug employed for uses other than An approved drug employed for uses other than those approved those approved

• Anew dosage form of an approved drug; and Anew dosage form of an approved drug; and • Even a drug used Even a drug used in vitroin vitro as a diagnostic agent as a diagnostic agent

when its uses will influence the diagnosis or when its uses will influence the diagnosis or treatment of disease in a human patienttreatment of disease in a human patient

INVESTIGATIONAL NEW INVESTIGATIONAL NEW DRUG APPLICATION (IND)DRUG APPLICATION (IND)

• The IND submitted to the FDA contains The IND submitted to the FDA contains the results of all preclinical the results of all preclinical investigations carried out in animals, investigations carried out in animals, including complete toxicity data, the full including complete toxicity data, the full pharmacologic spectrum of the drug pharmacologic spectrum of the drug and any studies of absorption, and any studies of absorption, distribution, biotransformation and distribution, biotransformation and excretion. In addition, the IND must excretion. In addition, the IND must provide the following information: provide the following information:

INVESTIGATIONAL NEW INVESTIGATIONAL NEW DRUG APPLICATION (IND)DRUG APPLICATION (IND)

• Complete composition of the drug, its source and Complete composition of the drug, its source and manufacturing data with details of all quality control manufacturing data with details of all quality control measures employed to ensure exact reproducibility measures employed to ensure exact reproducibility of manufacture and identification of all ingredients of manufacture and identification of all ingredients

• Specifications of the dosage forms to be given to Specifications of the dosage forms to be given to humans humans

• A description of the investigations to be undertaken, A description of the investigations to be undertaken, including the doses to be administered, the route including the doses to be administered, the route and duration of drug administration and the specific and duration of drug administration and the specific clinical observations and laboratory observations to clinical observations and laboratory observations to be performed be performed

• The names and the qualifications of and the The names and the qualifications of and the facilities available to, each investigator who will facilities available to, each investigator who will participate in the initial studies (Phase I) participate in the initial studies (Phase I)

INVESTIGATIONAL NEW INVESTIGATIONAL NEW DRUG APPLICATION (IND)DRUG APPLICATION (IND)– Copies of all informational material supplied Copies of all informational material supplied

to each investigator (the data sheets supplied to each investigator (the data sheets supplied to the investigator incorporate the data to the investigator incorporate the data supplied in the IND itself) supplied in the IND itself)

– An agreement from the sponsor to notify FDA An agreement from the sponsor to notify FDA and all investigators of any adverse effects and all investigators of any adverse effects that arise during either the continuing animal that arise during either the continuing animal studies or human tests studies or human tests

– Agreement to submit annual progress reports Agreement to submit annual progress reports – Certification that "informed consent" will be Certification that "informed consent" will be

obtained from the subjects or patients to obtained from the subjects or patients to whom the drug will be given whom the drug will be given

PHASE I STUDIESPHASE I STUDIES

• Requires an FDA approved IND to commence Requires an FDA approved IND to commence

• Conducted in normal healthy human volunteers Conducted in normal healthy human volunteers

• Performed under carefully controlled conditionsPerformed under carefully controlled conditions

• Toxicological and pharmacological data obtained Toxicological and pharmacological data obtained by a trained clinical pharmacologistby a trained clinical pharmacologist

• Drug first administered at one tenth the ultimate Drug first administered at one tenth the ultimate projected effective doseprojected effective dose

PHASE I STUDIESPHASE I STUDIES• Primary objective is to obtain a safe and tolerated Primary objective is to obtain a safe and tolerated

dose in humans dose in humans

• Parameters of absorption, metabolism and excretion Parameters of absorption, metabolism and excretion are measured are measured

• The pharmacokinetic study relies on measurements The pharmacokinetic study relies on measurements of levels of the test drug in blood and urine at various of levels of the test drug in blood and urine at various times after administration (route usually oral) times after administration (route usually oral)

• If drug is ineffective at the given dose, the above If drug is ineffective at the given dose, the above measurements resolve issues of efficacy vs. poor measurements resolve issues of efficacy vs. poor absorption or rapid eliminationabsorption or rapid elimination

PHASE II STUDIESPHASE II STUDIES

• Randomized control trials in patients Randomized control trials in patients with the disease for which the drug is with the disease for which the drug is intended or as a pretreatment to intended or as a pretreatment to prevent diseaseprevent disease

• Numbers of patients are limited, but Numbers of patients are limited, but may be up to several hundred may be up to several hundred

• Doses are higher than those in Phase IDoses are higher than those in Phase I• Studies may last several months to Studies may last several months to

two years two years

PHASE II STUDIESPHASE II STUDIES

• Safety still an important concern, but Safety still an important concern, but efficacy is the major emphasis efficacy is the major emphasis

• Flexibility in the design of studies is very Flexibility in the design of studies is very desirable at this stage desirable at this stage

• Extremely slow metabolism of drug with Extremely slow metabolism of drug with accumulation of subsequent doses and accumulation of subsequent doses and toxicity might require additional studies at toxicity might require additional studies at this point this point

• Changes in the original protocol require Changes in the original protocol require the submission of amendments to IND and the submission of amendments to IND and additional review by IRB’sadditional review by IRB’s

PHASE III STUDIESPHASE III STUDIES

• Large-scale controlled studies Large-scale controlled studies • Major objective is to develop data to Major objective is to develop data to

permit the drug to be marketed and used permit the drug to be marketed and used safely and effectively safely and effectively

• Multi-patient – multi-center study Multi-patient – multi-center study • May involve as many as 150 clinicians, May involve as many as 150 clinicians,

many of whom are experienced clinical many of whom are experienced clinical pharmacologistspharmacologists

• Usually involves 1500 to as many as 4000 Usually involves 1500 to as many as 4000 patientspatients

PHASE III STUDIESPHASE III STUDIES

• Study generally lasts anywhere from 2 –10 years Study generally lasts anywhere from 2 –10 years with an average length of 5 years with an average length of 5 years

• Study examines safety and effectiveness, but Study examines safety and effectiveness, but emphasizes proper dose determination emphasizes proper dose determination

• The following studies may be conducted at this The following studies may be conducted at this stage:stage:– drug biotransformation drug biotransformation – capacity of drug to bind to plasma proteins capacity of drug to bind to plasma proteins – to induce or inhibit enzymes to induce or inhibit enzymes – to interact in various ways with other drugs to interact in various ways with other drugs

THE NEW DRUG THE NEW DRUG APPLICATION (NDA)APPLICATION (NDA)

   • When the sponsor is convinced that the When the sponsor is convinced that the

data obtained in Phase III studies justify data obtained in Phase III studies justify approval for safety and efficacy for the approval for safety and efficacy for the use(s) intended, the NDA is submitted use(s) intended, the NDA is submitted

• Usually, at least 5 years has elapsed since Usually, at least 5 years has elapsed since the drug was originally screened the drug was originally screened

• The NDA contains all of the chemical, The NDA contains all of the chemical, pharmacologic, toxicologic., clinical and pharmacologic, toxicologic., clinical and maufacturing data that have been maufacturing data that have been collected in the whole process collected in the whole process

• The NDA also contains bioequivalence and The NDA also contains bioequivalence and bioavailability databioavailability data

THE NEW DRUG THE NEW DRUG APPLICATION (NDA)APPLICATION (NDA)

   • Samples of the drug, its labels and the Samples of the drug, its labels and the

package insert that will accompany the drug package insert that will accompany the drug in all shipments to physicians and pharmaciesin all shipments to physicians and pharmacies

• Submission of the NDA starts a "review Submission of the NDA starts a "review clock" in which the FDA has 180 days to clock" in which the FDA has 180 days to respond respond

• The NDA submission generally occurs The NDA submission generally occurs essentially when the sponsor and FDA agree essentially when the sponsor and FDA agree that studies are complete. Thus the NDA is that studies are complete. Thus the NDA is approved fairly promptly approved fairly promptly

• 926 NDA’s were approved between 1980 and 926 NDA’s were approved between 1980 and 19861986

THE NEW DRUG THE NEW DRUG APPLICATION (NDA)APPLICATION (NDA)

   • If the NDA is deemed for some reason to be If the NDA is deemed for some reason to be incomplete, the sponsor is required to incomplete, the sponsor is required to resubmit additional resubmit additional

• If there is a disagreement between FDA and If there is a disagreement between FDA and the sponsor then a hearing may be held and the sponsor then a hearing may be held and the outcome is appealable in Courtthe outcome is appealable in Court

• Less than 25% of all new drugs for Less than 25% of all new drugs for marketing are novel or new molecular marketing are novel or new molecular entities (NME’s). The rest are new salts, new entities (NME’s). The rest are new salts, new formulations, new indications or duplicates formulations, new indications or duplicates of drugs previously approved for marketingof drugs previously approved for marketing

   

PHASE IV – PHASE IV – POSTMARKETING POSTMARKETING SURVEILLANCESURVEILLANCE

• Applies to all aspects of investigation Applies to all aspects of investigation following NDA approval and general following NDA approval and general availability of drug in widespread clinical use availability of drug in widespread clinical use

• Claims for safety and efficacy appearing or Claims for safety and efficacy appearing or advertising are reviewed and approved by advertising are reviewed and approved by FDAFDA

• Reports concerning clinical studies must be Reports concerning clinical studies must be sent to FDA:sent to FDA:– every three months during the first year every three months during the first year – every six months in the second year every six months in the second year – annually thereafter annually thereafter

PHASE IV – PHASE IV – POSTMARKETING POSTMARKETING SURVEILLANCESURVEILLANCE

• Reports must include the following Reports must include the following information about:information about:– quantity of drug distributed quantity of drug distributed – copies of mailing pieces and labeling copies of mailing pieces and labeling – examples of advertising for prescription drugs examples of advertising for prescription drugs

• Immediate reports on unexpected side-Immediate reports on unexpected side-effects, injury, toxic or allergic reactions effects, injury, toxic or allergic reactions and failure of the drug to exert its and failure of the drug to exert its expected pharmacologic reactionexpected pharmacologic reaction

CLASSIFICATION SYSTEMCLASSIFICATION SYSTEMType - Review Priorities Type - Review Priorities

• New Molecular Entity (NME)New Molecular Entity (NME)

P - Priority review – clear therapeutic gain P - Priority review – clear therapeutic gain

• New salt New salt

S– Std Review – similar to previously S– Std Review – similar to previously marketed drug marketed drug

• New Formulation New Formulation

• New Combination New Combination

AA – AIDS/HIV – Related AA – AIDS/HIV – Related

CLASSIFICATION SYSTEMCLASSIFICATION SYSTEMType - Review Priorities Type - Review Priorities

• Already Marketed Drug Product – Already Marketed Drug Product – Duplication (New MFR)Duplication (New MFR)

V – Designated Orphan Drug or E -V – Designated Orphan Drug or E -Subpart E DrugSubpart E Drug

• New Claim for already Marketed Drug New Claim for already Marketed Drug F – Pending Outcome of Validity F – Pending Outcome of Validity

Assessment Assessment • Already Marketed Drug Product – No Already Marketed Drug Product – No

Approved NDA Approved NDA G – Data ValidatedG – Data Validated