Investigational Drugs

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Investigational Drugs

• Drug Laws, Drug Approval Process

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History of Drug Development Regulation in the US

• Import Drug Act of 1848 passed after it was
  discovered that US troops in Mexican War were
  given substandard drugs.
• Purpose provide for inspection, detention and
  destruction or re-export of imported drug
  shipments that failed to meet US standards

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History...

• Pure Food and Drug Act of 1906
• Required that drugs not be mislabeled or
  adulterated and they must meet recognized
  standards for strength and purity
• Mislabeling identity or composition of drugs
• Sherley Amendment 1912
• Prohibited false therapeutic claims for drugs

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History.

• Food, Drug and Cosmetic Act 1938
• After 107 people died after taking sulfanilamide
  prepared in diethylene glycol (solvent similar to
  ethylene glycol (antifreeze)
• Purpose require safety of drugs when used in
  accordance with the labeled instructions be
  proven through testing before marketing
• Submission of NDA to the FDA first established

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History.

• Durham-Humphrey Amendment 1951
• Purpose divide drugs into 2 categories
• OTC (safely self-administered)
• Rx (potentially dangerous side effects- required
  medical expert supervision)
• Required following statement on all Rx labels
  Caution Federal Law prohibits dispensing
  without a prescription

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History...

• Kefauver-Harris Drug Amendment 1962
• Purpose 1)Manufacturer has to demonstrate proof
  of _________and _______ prior to marketing any
  new drug. 2) manufacturer comply with CGMP
  (current good manufacturing practices. 3) FDA has
  to formally approve an NDA before drug is
  marketed.

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History...

• 1992 PDUFA (Prescription Drug User Fee Act)
  Defines time frames for NDA reviews and
  establishes revenues to fund increased demands on
  new time frames for approval process.
• 1997 FDAMA (Food and Drug Administration
  Modernization Act) Allows other technology to
  facilitate regulatory review process (FAX,
  Internet etc)

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History...

• ICH (International Conference on Harmonization)
  Cooperation between Japan, Europe, US to develop
  common guidelines for ensuring quality, safety,
  and efficacy of drugs between countries.
• Goal ensure a method for submission and rapid
  regulatory approval in approval process and
  availability world wide

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Drug Approval ProcessStep 1

• Pre-Clinical Drug testing
• In vitro or animal testing
• Develop a pharmacologic profile of the drug
• Determine acute toxicity in at least two species
  of animals
• Conduct short term toxicity studies (2 weeks- 3
  months)

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Investigational New Drug Application (IND)

• File IND with the FDA
• Contains chemical information, preclinical data,
  detailed description of planned clinical trials.
• Purpose to get approval to begin clinical trials
  in humans.
• It can only be filed after the study sponsor has
  identified the pharmacological profile of the
  drug and has results from both acute and short
  term toxicity studies in animals.

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FDA Responsibilities for the IND

• IND will be forwarded to one of nine divisions
  for review based on therapeutic category of the
  drug
• FDA has ____ days after the receipt of the IND to
  respond to the sponsor.
• After this 30 days the sponsor can begin clinical
  trials if no response from FDA w/in 30 days. FDA
  will respond with a clinical hold w/in 30 days
  to stop clinical trial initiation.

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Clinical Trial PhasesPhase 1

• Purpose determine basic safety and pharmacologic
  information.
• To identify preferred route
• To identify safe dosage range
• To identify toxicity
• Pharmacokinetics
• Treat 20-80 patients over 6 months-1 year
• healthy adult volunteers w/ no pre-existing
  conditions, or in patients who have exhausted all
  other options (cancer patients, AIDs patients)
• use cautious (low) dosages

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Phases of Clinical TrialsPhase II

• Purpose Evaluate the study drug in subjects who
  suffer from the disease or condition that the
  drug is proposed to treat.
• Evaluate efficacy
• Identify group of patients most likely to benefit
• Treat 100-200 patients over 2 year duration

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Phases of Clinical TrialsPhase III

• Purpose Further define efficacy and safety
• New agent compared to current therapy
• Trials usually multicenter studies
• Treat 600-1000 patients
• Last 3 years
• These trials serve as basis for ______ for
  marketing approval

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New Drug Application (NDA)

• After phase 3 trials completed, sponsor submits
  NDA to the FDA requesting approval for marketing.
• Includes pre-clinical data, clinical data,2 well
  designed controlled clinical trials info,
  manufacturing methods,kinetics, pharmacology,
  product quality assurance, relevant foreign
  clinical testing, published reports, proposed
  package insert for drug.

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Phase IV (Post Surveillance Studies)

• Drug is on the market.
• Purpose gather more data on safety and efficacy
  and identify an advantage over other therapies
• These are conducted for the approved indication,
  but may evaluate
• different doses
• effects of extended therapy
• drugs safety in other populations (pregnancy,
  children, elderly)
• New indications

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Drug to Market Approval Process

• Initial synthesis of an agent to approval of NDA
  8-9 years.
• NDA process ave. 2 years (2 mo.-7 yrs)
• Procedures to expedite process for AIDs, Cancer
  drugs etc.
• Emergency Use IND
• Parallel track
• Treatment IND
• Compassionate IND

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Emergency Use IND

• Purpose allow shipment of drug by sponsor for
  desperately ill patients prior to the submission
  of an IND.
• Can only be used for life threatening diseases
  where all other options have been exhausted.
• FDA approval required and must authorize
• IRB approval not required

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Parallel Track

• Purpose increase accessibility of experimental
  drugs for AIDS patients.
• Drug becomes available after phase I studies to
  patients who are ineligible for enrollment via
  controlled trials and are unable to benefit from
  current therapies.
• Drug is still monitored for safety and efficacy
  while clinical trials going.

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Treatment IND

• Purpose accessibility of experimental drugs for
  desperately ill patients.
• Criteria for use
• drug must be intended to treat a serious or
  immediately life threatening disease.
• No other alternative therapies
• Drug is under investigation in CCT (clinical
  trials)
• Sponsor must be actively pursuing FDA approval

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Treatment IND

• 2 categories of treatment IND
• life threatening conditions (death likely in
  months)
• Tx allowed with drug after phase II but earlier
  than phase III.
• serious conditions (disease causes irreversible
  morbidity- Alzheimers)
• tougher requirements for safety and efficacy
• tx allowed with drug during phase III or later.

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Compassionate Use IND

• Individual investigator IND
• allow release of drug for use on a single patient
  basis.
• Use this IND to obtain a drug from a foreign
  country for emergency use in a single patient.
• Both FDA and IRB approval are required.

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Expedited Approval Process

• Accelerated Drug Approval Program
• Used when drug is intended for tx of serious or
  life threatening condition and no other drug
  works in same way for condition.
• Can be approved as early as post-phase II.
• Needs 2 pivotal phase II studies completed.
• FDA can put restrictions on marketing and
  distribution

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Orphan Drug Act (1983)

• Provides incentives for manufacturers to develop
  orphan drugs
• Orphan drug Drug used for tx of a rare disease
  (affecting fewer than 200,000 people in US) or
  one that will not generate enough revenue to
  justify the costs of research and development.

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Orphan Drug Act Incentives

• Tax incentives sponsor is eligible to receive
  50 tax credit for money spent on RD
• Protocol assistance if drug shown to be used for
  rare disease, FDA will provide assistance in
  pre-clinical and clinical trials
• Grants and contracts FDA budget may allot up to
  12 million/yr for developing orphan drugs
• Marketing exclusivity 1st sponsor of orphan drug
  is allowed 7 years of marketing exclusivity for
  that indication.

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Generic Drug Approval Process

• Manufacturer submits an Abbreviated New Drug
  Application (ANDA) to obtain FDA approval to
  market the drug.
• ANDA data is submitted to the Center for Drug
  Evaluation and Research (CDER).
• CDER provides the review and approval of a
  generic drug product.

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CDER (Center for Drug Evaluation and Research)

• Approves generic drugs manufactured in the US
• checks patent laws before approval
• Approves imported drug products
• prevents unapproved new drugs or misbranded drugs
  from entering our country.
• Issue product certifications to foreign
  governments-- state that these products are
  manufactured according to the GMP (good
  manufacturing practice) bylaws.

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Generic Drug Manufacturer Requirements

• Document its compliance with GMP
• Provides full description of facilities used for
  manufacturing, packaging, labeling, and quality
  control
• Demonstrates bioequivalence to the brand drug
• Provide a chemistry review to assure it is manuf.
  in a reproducible manner under controlled
  conditions

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Role of the Pharmacist in Investigational Drug
Process

• Serving on the Institutional Review Board (IRB)-
  sets up guidelines, reviews financial
  evaluations, review of proposal to investigate
• Disseminating communication (preparation of DDS
  (drug data sheets), protocols for IDP
• Accountability records of drug usage
• Ordering, maintaining, returning drug supplies
  for clinical trials
• Randomizing and blinding drugs for trials
• Reporting adverse events
• Preparing the IND

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Investigational Drug Procedure (IDP)

• When reviewing protocol for clinical trial, it
  should contain
• Name and synonyms of study drug
• Chemical structure of study drug
• Mechanism of action of study drug
• Dosage range, route of administration
• Animal toxicologic and pharmacologic info
• Dosage form and strength to be supplied
• Preparation guidelines (stability, compatibility)
• Storage requirements, toxicities

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Drug Data Sheet (for use by Pharmacy, Nursing,
MDs)

• Drug name and synonyms, status, chairperson of
  study
• Therapeutic class, mechanism of action
• Pharmaceutical data
• Stability and storage data
• Dose preparation guidelines
• Usual dosage range, route of administration
• Side effects, toxicities
• Effective dates
• References