1. DRUG DEVELOPMENT
AND REGULATION
Joseph Hanig, Ph.D.

2. Historical Background
Why were Laws Needed?
• Adulteration for economic gain
• Early English Law - King John promulgates
rules on contamination of flour – Assizes of
Bread
• Quack medicines, hidden ingredients,
misbranding in early America
• American meat products rejected by Europe
• Publication of The Jungle by Upton Sinclair
• Tetanus contaminated diphtheria vaccine

3. Virus Toxin Act of 1902
• premarket clearance for safety and
efficacy
• factory inspection
• batch certification

4. Food and Drug Act of l906
(Wiley or Heyburn Act)
• first main federal drug law
• targeted adulteration and misbranding
• established the U.S. Pharmacopeia and
National Formulary to establish and
regulate reference standards

5. The Sherley Amendment of
l912
• prohibited use of fraudulent therapeutic
claims
• placed burden of proof on government
and resulted in weak or non-enforcement
due to the paucity of modern scientific
techniques and tools

6. The Food, Drug and Cosmetic
Act of l938 (Copeland Act)
• premarket clearance for safety only
• factory inspection instituted
• drug could become approved if FDA did
not act within a specified deadline

7. The Federal Insecticide,
Fungicide and Rodenticide Act
(FIFRA) Act – l947
• defined the LD-50
• established classes of toxicity based on order of
magnitude of dose producing an LD-50
• require a label to be written for a pesticide as
well as registration with USDA

8. The Durham Humphrey
Amendment of l951
• defined the modern practice of pharmacy
• established pharmacist - physician relationship
• established a separate class for narcotics and
physician registration numbers
• deals with "Legend Drugs" – drugs which bear
the warning "Caution Federal Law Prohibits
Dispensing Without Prescription" e.g. Rx drug

9. Insulin and Antibiotic
Certification Amendments ’41,
’43, ’45, ’49, ’52
• required batch certification of all Master
Lots (bulk product) as well as all lots of
finished product
• required batch certification of all lots of
antibiotics before they could be sold

10. The Kefauver – Harris Act of
l962
• premarket clearance for safety and efficacy
• establishment of "Investigational Exemption for a New
Drug (IND) which required animal data to be submitted
and evaluated before clinical trial could begin
• established 3 phases of clinical testing
• made approval or denial of an NDA an FDA requirement
rather than the default approval of the 1938 law
• established modern drug review and approval
procedures

11. DESI Evaluation of l966;
completed l969-70
Established panels that rated pre 1966
drugs as: effective; probably effective;
possibly effective and ineffective and
drove the last two categories off the
market unless new evidence was
presented

12. Comprehensive Drug Abuse
Prevention and Control Act of
1970
• Established the DEA in the Dept of Justice
• Established 5 schedules for drugs of abuse
• Established penalties for misuse
• Established quotas for manufacturing of
narcotics

13. Important Legislative
Developments of the 70’s
• Over-the-Counter (OTC) Evaluation Monographs
l972 – present
• Supreme Court Ruling of 1973 concerning the
authority of FDA
• Drug Listing Act of l972
• Good Laboratory Practices regulations; proposed
1976; finalized l979

14. Orphan Drug Act of 1983
• defined orphan drugs
• encouraged their manufacture by giving
companies exclusivity and tax relief

15. Drug Price Competition and
Patent Term Restoration Act –
1984
• established the "so called" generic drug
• established the concept of bioequivalence for generic
drugs (+ 20% of the rate and extent of absorption of
the innovator drug and the generic is considered to be
equivalent to the innovator brand)
• established the abbreviated NDA called ANDA that did
not require a repeat of safety and efficacy studies of the
innovators, just bioequivalency studies

16. Generic Drugs Act – 1990
• established criteria and standards for
generic drug manufacture
• established the FDA Office of generic
drugs to oversee the law and administer
the approval process

17. Prescription Drug User Fee Act
(PDUFA) of l994; l997; 2000;
2003
• industry provides FDA funds in the form of
fees to pay for positions and resources to
review new drug application
• review time speeded up and drug lag
shortened

18. FDA Modernization Act - l997
• abolishes insulin certification
• abolishes antibiotic monographs

19. Pediatric Exclusivity Act of
1998
• Provides for FDA to request non-manditory
research studies on drugs with toxicity
issues that are used in children
• Provides exclusivity or drug patent
extension for those companies willing to
perform these voluntary studies

20. Drug Development - Methods
used to identify compounds
with potential therapeutic
usefulness
• Screening – most new drugs discovered this
way
• screen is a specified set of procedures to which
a series of compounds is subjected to both in
vivo and in vitro
• quantitative part of screening is the bioassay
• bioassay used to establish relationship between
dose and response and compare unknowns to
standards

21. Synthesis, Purification & Data
Mining
• Synthesis of drug de novo
• Modification of structure of existing drugs –
structure – activity studies (SAR)
• Purification of drugs from natural sources such
as native, folklore or herbal medicines
• Exploration of side effects of existing drugs -
awareness of potential usefulness of side
effects

22. Animal Studies - Preclinical
Studies
Acute toxicity tests
• one administration of chemical to each animal
• generation of dose – response curves
• Appropriate pharmacological testing to determine
ED50
• Develop analytical methods for determining
absorption, excretion, distribution and
metabolism of chemical

23. Animal Studies - Preclinical
Studies
– Subchronic toxicity tests
• usually 60 –90 days duration
• multiple administrations or continuous
exposure via food or water to one dose
level of a chemical per animal

24. Animal Studies - Preclinical
Studies
• Chronic toxicity tests
– 2 to 5 years duration depending on
species
– multiple administrations or continuous
exposure via food or water to one dose
level of a chemical per animal

25. Clinical Studies
– Notice of Claimed Investigational Exception
for a New Drug (IND)
– Phase I of clinical studies
– pharmacological investigation
– one or two clinical pharmacologists
– healthy volunteers – informed consent – one
tenth of dose for PK studies

26. Clinical Studies (continued)
Phase II of clinical studies
– initial controlled clinical evaluation
– more than two clinical pharmacologists
– selected volunteer patients with specific
disease indication for drug
– double blind studies

27. Clinical Studies (continued)
Phase III of clinical studies
– extended clinical evaluation
– usually 50 – 100 clinicians
– usually 500 – 1000 patients

28. 8

29. DEFINITION OF A NEW DRUG
• Any chemical or substance not previously used
in humans for the treatment of a disease
• Combinations of approved drugs or of old drugs
even though the individual components are not
new drugs
• An approved drug employed for uses other than
those approved
• Anew dosage form of an approved drug; and
• Even a drug used in vitro as a diagnostic agent
when its uses will influence the diagnosis or
treatment of disease in a human patient

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

31. INVESTIGATIONAL NEW DRUG
APPLICATION (IND)
• Complete composition of the drug, its source and
manufacturing data with details of all quality control
measures employed to ensure exact reproducibility of
manufacture and identification of all ingredients
• Specifications of the dosage forms to be given to
humans
• A description of the investigations to be undertaken,
including the doses to be administered, the route and
duration of drug administration and the specific clinical
observations and laboratory observations to be
performed
• The names and the qualifications of and the facilities
available to, each investigator who will participate in the
initial studies (Phase I)

32. INVESTIGATIONAL NEW DRUG
APPLICATION (IND)
– Copies of all informational material supplied
to each investigator (the data sheets supplied
to the investigator incorporate the data
supplied in the IND itself)
– An agreement from the sponsor to notify FDA
and all investigators of any adverse effects
that arise during either the continuing animal
studies or human tests
– Agreement to submit annual progress reports
– Certification that "informed consent" will be
obtained from the subjects or patients to
whom the drug will be given

33. PHASE I STUDIES
• Requires an FDA approved IND to commence
• Conducted in normal healthy human volunteers
• Performed under carefully controlled conditions
• Toxicological and pharmacological data
obtained by a trained clinical pharmacologist
• Drug first administered at one tenth the
ultimate projected effective dose

34. PHASE I STUDIES
• Primary objective is to obtain a safe and
tolerated dose in humans
• Parameters of absorption, metabolism and
excretion are measured
• The pharmacokinetic study relies on
measurements of levels of the test drug in blood
and urine at various times after administration
(route usually oral)
• If drug is ineffective at the given dose, the
above measurements resolve issues of efficacy
vs. poor absorption or rapid elimination

35. PHASE II STUDIES
• Randomized control trials in patients with
the disease for which the drug is intended
or as a pretreatment to prevent disease
• Numbers of patients are limited, but may
be up to several hundred
• Doses are higher than those in Phase I
• Studies may last several months to two
years

36. PHASE II STUDIES
• Safety still an important concern, but efficacy is
the major emphasis
• Flexibility in the design of studies is very
desirable at this stage
• Extremely slow metabolism of drug with
accumulation of subsequent doses and toxicity
might require additional studies at this point
• Changes in the original protocol require the
submission of amendments to IND and
additional review by IRB’s

37. PHASE III STUDIES
• Large-scale controlled studies
• Major objective is to develop data to permit the
drug to be marketed and used safely and
effectively
• Multi-patient – multi-center study
• May involve as many as 150 clinicians, many of
whom are experienced clinical pharmacologists
• Usually involves 1500 to as many as 4000
patients

38. PHASE III STUDIES
• Study generally lasts anywhere from 2 –10 years with
an average length of 5 years
• Study examines safety and effectiveness, but
emphasizes proper dose determination
• The following studies may be conducted at this stage:
– drug biotransformation
– capacity of drug to bind to plasma proteins
– to induce or inhibit enzymes
– to interact in various ways with other drugs

39. THE NEW DRUG APPLICATION
(NDA)
• When the sponsor is convinced that the data
obtained in Phase III studies justify approval for
safety and efficacy for the use(s) intended, the
NDA is submitted
• Usually, at least 5 years has elapsed since the
drug was originally screened
• The NDA contains all of the chemical,
pharmacologic, toxicologic., clinical and
maufacturing data that have been collected in
the whole process
• The NDA also contains bioequivalence and
bioavailability data

40. THE NEW DRUG APPLICATION
(NDA)
• Samples of the drug, its labels and the package
insert that will accompany the drug in all
shipments to physicians and pharmacies
• Submission of the NDA starts a "review clock"
in which the FDA has 180 days to respond
• The NDA submission generally occurs
essentially when the sponsor and FDA agree
that studies are complete. Thus the NDA is
approved fairly promptly
• 926 NDA’s were approved between 1980 and
1986

41. THE NEW DRUG APPLICATION
(NDA)
• If the NDA is deemed for some reason to be
incomplete, the sponsor is required to resubmit
additional
• If there is a disagreement between FDA and the
sponsor then a hearing may be held and the
outcome is appealable in Court
• Less than 25% of all new drugs for marketing
are novel or new molecular entities (NME’s).
The rest are new salts, new formulations, new
indications or duplicates of drugs previously
approved for marketing

42. PHASE IV – POSTMARKETING
SURVEILLANCE
• Applies to all aspects of investigation following
NDA approval and general availability of drug in
widespread clinical use
• Claims for safety and efficacy appearing or
advertising are reviewed and approved by FDA
• Reports concerning clinical studies must be sent
to FDA:
– every three months during the first year
– every six months in the second year
– annually thereafter

43. PHASE IV – POSTMARKETING
SURVEILLANCE
• Reports must include the following information
about:
– quantity of drug distributed
– copies of mailing pieces and labeling
– examples of advertising for prescription drugs
• Immediate reports on unexpected side-effects,
injury, toxic or allergic reactions and failure of
the drug to exert its expected pharmacologic
reaction

44. CLASSIFICATION SYSTEM
Type - Review Priorities
• New Molecular Entity (NME)
P - Priority review – clear therapeutic gain
• New salt
S– Std Review – similar to previously
marketed drug
• New Formulation
• New Combination
AA – AIDS/HIV – Related

45. CLASSIFICATION SYSTEM
Type - Review Priorities
• Already Marketed Drug Product – Duplication
(New MFR)
V – Designated Orphan Drug or E -Subpart E
Drug
• New Claim for already Marketed Drug
F – Pending Outcome of Validity Assessment
• Already Marketed Drug Product – No Approved
NDA
G – Data Validated