Investigational Drugs

Drug Laws, Drug Approval Process

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

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

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

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”

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.

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)

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

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)

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.

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.

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, AID’s patients)

– use cautious (low) dosages

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

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

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.

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– drug’s safety in other populations

(pregnancy, children, elderly)– New indications

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 AID’s,

Cancer drugs etc.:– Emergency Use IND – Parallel track– Treatment IND– Compassionate IND

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

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.

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

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- Alzheimer’s)

• tougher requirements for safety and efficacy• tx allowed with drug during phase III or later.

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.

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

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.

Orphan Drug Act Incentives• Tax incentives: sponsor is eligible to receive

50% tax credit for money spent on R&D • 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.

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.

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.

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

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

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

Drug Data Sheet (for use by Pharmacy, Nursing, MD’s)

• 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