FEDERAL REGULATIONS & DRUG DEVELOPMENT

Joseph Hanig, Ph.D.

OUTLINE

  1. Introductory remarks
    1. Historical background leading to the development of Federal Legislation for foods, drugs and cosmetics
    2. Major drug legislation
    1. Virus  Toxin Act of 1902
    1. premarket clearance for safety and efficacy
    2. factory inspection
    3. batch certification
    1. Food and Drug Act of l906 (Wiley or Heyburn Act)
    1. first main federal drug law
    2. targeted adulteration and misbranding
    3. established the U.S. Pharmacopeia and National Formulary to establish and regulate reference standards
    1. The Sherley Amendment of l912
    1. prohibited use of fraudulent therapeutic claims
    2. placed burden of proof on government and resulted in weak or non-enforcement due to the paucity of modern scientific techniques and tools
    1. The Food, Drug and Cosmetic Act of l938 (Copeland Act)
    1. premarket clearance for safety only
    2. factory inspection instituted
    3. drug could become approved if FDA did not act within a specified deadline

5. The Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Act – l947

    1. defined the LD-50
    2. established classes of toxicity based on order of magnitude of dose producing an LD-50
    3. require a label to be written for a pesticide as well as registration with USDA
    1. The Miller Amendment of l948
    1. The Delaney Committee of l950
    2. The Durham Humphrey Amendment of l951
    1. defined the modern practice of pharmacy
    2. established pharmacist - physician relationship
    3. established a separate class for narcotics and physician registration numbers
    4. 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

    1. required batch certification of all Master Lots (bulk product) as well as all lots of finished product
    2. required batch certification of all lots of antibiotics before they could be sold
    1. The Kefauver – Harris Act of l962
    1. premarket clearance for safety and efficacy
    2. Establishment of "Investigational Exemption for a New Drug (IND) which required animal data to be submitted and evaluated before clinical trial could begin
    3. Established 3 phases of clinical testing
    4. made approval or denial of an NDA an FDA requirement rather than the default approval of the 1938 law
    5. established modern drug review and approval procedures
    1. DESI Evaluation of l966; completed l969-70

      2. 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

    2. Animal Drug Amendments of 1968
    3. Comprehensive Drug Abuse Prevention and Control Act of 1970
    1. Established the DEA in the Dept of Justice
    2. Established 5 schedules for drugs of abuse
    3. Established penalties for misuse
    4. Established quotas for manufacturing of narcotics
    1. Over-the-Counter (OTC) Evaluation Monographs l972 – present
    2. Supreme Court Ruling of 1973 concerning the authority of FDA
    3. Drug Listing Act of l972
    4. Good Laboratory Practices regulations; proposed 1976; finalized l979
    5. Orphan Drug Act of 1983

a. defined orphan drugs

    1. encouraged their manufacture by giving companies exclusivity and tax relief
    1. Drug Price Competition and Patent Term Restoration Act – 1984

a. established the "so called" generic drug

    1. 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)
    2. established the abbreviated NDA called ANDA that did not require a repeat of safety and efficacy studies of the innovators, just bioequivalency studies
    1. Generic Drugs Act – 1990
    1. established criteria and standards for generic drug manufacture
    2. established the FDA Office of generic drugs to oversee the law and administer the approval process
    1. Prescription Drug User Fee Act (PDUFA) of l994; l997
    1. industry provides FDA funds in the form of fee to pay for positions and resources to review new drug application
    2. review time speeded up and drug lag shortened
    1. FDA Modernization Act - l997
    1. abolishes insulin certification
    2. abolishes antibiotic monographs
  1. Drug Development
    1. Methods used to identify compounds with potential therapeutic usefulness
    1. Screening – most new drugs discovered this way
    1. screen is a specified set of procedures to which a series of compounds is subjected to both in vivo and in vitro
    2. quantitative part of screening is the bioassay
    3. bioassay used to establish relationship between dose and response and compare unknowns to standards
    1. Purification of drugs from natural sources such as native, folklore or herbal medicines
    2. Synthesis of drug de novo
    3. Exploration of side effects of existing drugs
    1. awareness of potential usefulness of side effects
    1. Modification of structure of existing drugs – structure – activity studies (SAR)
    1. Animal Studies (Preclinical Studies)
    1. Acute toxicity tests
    1. one administration of chemical to each animal
    2. generation of dose – response curves
    1. Subchronic toxicity tests
    1. usually 60 –90 days duration
    2. multiple administrations or continuous exposure via food or water to one dose level of a chemical per animal
    1. Chronic toxicity tests
    1. 2 to 5 years duration depending on species
    2. multiple administrations or continuous exposure via food or water to one dose level of a chemical per animal
    1. Appropriate pharmacological testing to determine ED50
    2. Develop analytical methods for determining absorption, excretion, distribution and metabolism of chemical
    1. Clinical Studies
    1. Notice of Claimed Investigational Exception for a New Drug (IND)
    2. Phase I of clinical studies
    1. pharmacological investigation
    2. one or two clinical pharmacologists
    3. healthy volunteers – informed consent – one tenth of dose for PK studies
    1. Phase II of clinical studies
    1. initial controlled clinical evaluation
    2. more than two clinical pharmacologists
    3. selected volunteer patients with specific disease indication for drug
    4. double blind studies
    1. Phase III of clinical studies
    1. extended clinical evaluation
    2. usually 50 – 100 clinicians
    3. usually 500 – 1000 patients

     

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

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:

    1. 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
    2. Specifications of the dosage forms to be given to humans
    3. 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
    4. The names and the qualifications of and the facilities available to, each investigator who will participate in the initial studies (Phase I)
    5. Copies of all informational material supplied to each investigator (the data sheets supplied to the investigator incorporate the data supplied in the IND itself)
    6. 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
    7. Agreement to submit annual progress reports
    8. Certification that "informed consent" will be obtained from the subjects or patients to whom the drug will be given

Investigations in humans may begin as soon as FDA has indicated its approval, or 30 days from submission of the IND if no formal notice has been received.

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
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

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
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

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
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:

    1. drug biotransformation
    2. capacity of drug to bind to plasma proteins
    3. to induce or inhibit enzymes
    4. to interact in various ways with other drugs

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

 

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:

    1. every three months during the first year
    2. every six months in the second year
    3. annually thereafter
Reports must include the following information about:
    1. quantity of drug distributed
    2. copies of mailing pieces and labeling
    3. 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

CLASSIFICATION SYSTEM

Types Review Priorities

  1. New Molecular Entity (NME)P - Priority review – clear therapeutic gain
  2. New saltS – Std Review – similar to prev. marketed

Drug

3. New Formulation

4. New Combination AA – AIDS/HIV – Related

  1. Already Marketed DrugV – Designated Orphan Drug

    2. Product – Duplication E – Subpart E Drug

    (New MFR)

  2. New Claim for already N - OTC

    3. Marketed Drug F – Pending Outcome of Validity

  3. Already Marketed Drug Assessment

Product – No Approved NDA G – Data Validated