Accutane FDA (Section Name - Saver’s Initials) 3/9/00 12:50 PM 1 Risk Management Options Russell Ellison, MD Chief Medical Officer Vice President, Medical Affairs Roche Laboratories, Inc.

Accutane and Pregnancy Accutane use is increasing Accutane use is increasing The pregnancy rate is declining The pregnancy rate is declining The pregnancy rate in women on Accutane is about 80-90% less than for those with normal contraceptive use (0.3% vs. 1-5%) The pregnancy rate in women on Accutane is about 80-90% less than for those with normal contraceptive use (0.3% vs. 1-5%) For every 1000 women treated with Accutane, pregnancy has not occurred in 997 For every 1000 women treated with Accutane, pregnancy has not occurred in 997

The absolute goal is the prevention of pregnancy

HOWEVER: While an individual’s risk of pregnancy is decreasing, the total public health burden has not. While an individual’s risk of pregnancy is decreasing, the total public health burden has not. i.e: the absolute number of exposed pregnancies has not decreased i.e: the absolute number of exposed pregnancies has not decreased

To Prevent Pregnancy Every patient has to avoid pregnancy every day of therapy Every patient has to avoid pregnancy every day of therapy –1st trimester teratogens require patient not to be pregnant at start of treatment or to become pregnant during treatment as well –later trimester teratogens require the physician to avoid prescription during pregnancy

FDA OPTIONS: TPPP PLUS Option 1.. Mandatory registration of all female patients External data sources monitoring program impact Option 2 #1 plus No dispensing unless pharmacist confirms a documented negative pregnancy prevention test Option 3 #2 plus Pharmacist confirms that appropriate patient compliance with contraceptive practices, drug sharing and blood donation guidelines has been documented Option 4 #3 plus Pharmacists would have to be trained, registered, and authorized before allowed to dispense Accutane

every woman must avoid pregnancy every day Mandatory Programs Try to obtain compliance through conditional access to the drug, does not achieve active participation through motivation and knowledge Try to obtain compliance through conditional access to the drug, does not achieve active participation through motivation and knowledge Require a single channel of distribution and access to the drug Require a single channel of distribution and access to the drug

every woman must avoid pregnancy every day Mandatory Programs Stress completeness of documentation of compliance (in public at the pharmacy counter), not effectiveness of practice Stress completeness of documentation of compliance (in public at the pharmacy counter), not effectiveness of practice Enforce a population standard for all patients; not an optimal program for the individual Enforce a population standard for all patients; not an optimal program for the individual

every woman must avoid pregnancy every day Mandatory Programs Through the manufacturer, to be implemented by the pharmacist: Through the manufacturer, to be implemented by the pharmacist: –require additional qualifications or conditions from the prescriber to be fulfilled for the dispensing of a drug beyond the State’s licensure of the prescriber and/or the State Medical Board’s regulations

every woman must avoid pregnancy every day Mandatory Programs The pharmacist is now being asked to control the behavior of the doctor and the patient… The pharmacist is now being asked to control the behavior of the doctor and the patient… Is this appropriate? Is this feasible?

FDA OPTIONS: TPPP PLUS Option 1.. Mandatory registration of all female patients External data sources monitoring program impact Option 2 #1 plus No dispensing unless pharmacist confirms a documented negative pregnancy prevention test Option 3 #2 plus Pharmacist confirms that appropriate patient compliance with contraceptive practices, drug sharing and blood donation guidelines has been documented Option 4 #3 plus Pharmacists would have to be trained, registered, and authorized before allowed to dispense Accutane

every woman must avoid pregnancy every day Mandatory Registration Does not reduce the risk of pregnancy Does not reduce the risk of pregnancy Only benefit is a denominator of 100% Only benefit is a denominator of 100% Coercive: condition of drug is public registry vs. private consent Coercive: condition of drug is public registry vs. private consent Considerable risk of poor follow-up (response) and reliability and chance of erroneously low pregnancy and compliance rates Considerable risk of poor follow-up (response) and reliability and chance of erroneously low pregnancy and compliance rates

every woman must avoid pregnancy every day Mandatory Programs Common feature of all four options: Common feature of all four options: Excessive burden on physicians and patients with no perceived individual benefit Will produce an indiscriminate barrier to access

Risk Management Programs: Pregnancy What experience do we have? Accutane PPP: voluntary, initiated 1989 Accutane PPP: voluntary, initiated 1989 –evaluated, published, publicly reviewed –pregnancy rate known with tight CI –successful at reducing individual risk from normal contraceptive practice –200,000 women treated per year –young healthy patients –well known unique drug –alternate channels available

Risk Management Program - TPPP

Risk Management Programs: Pregnancy What experience do we have? STEPS (Thalidomide) mandatory, introduced 1997 STEPS (Thalidomide) mandatory, introduced 1997 –basic design is publicly known –no evaluation or review of results publicly available –small population (majority are ill, older women) –>50% have malignancies –alternate channels for patient access??

Based on what we know, and balancing: Based on what we know, and balancing: –likelihood of success –risk of compromising current success –risk of denying treatment to patients who would not become pregnant

To prevent pregnancy in women prescribed Accutane, mandatory programs : To prevent pregnancy in women prescribed Accutane, mandatory programs : –are untested –have unknown benefits over the T-PPP and unquantifiable risks which will be difficult to ascertain and reverse

every woman must avoid pregnancy every day Pregnancy Prevention for women taking Accutane is a shared responsibility of: Pregnancy Prevention for women taking Accutane is a shared responsibility of: –Roche –Prescriber –Pharmacist, nurse, reproductive health professional –PATIENT The TPPP is the best method to assure active participation of all parties to prevent pregnancy, and has the optimal chance of success with least risk The TPPP is the best method to assure active participation of all parties to prevent pregnancy, and has the optimal chance of success with least risk

Roche is committed to the absolute goal of pregnancy prevention and the continual improvement of the TPPP