Record of Proceedings for the Scientific Advisory Panel on Isotretinoin Risk Management (SAP-IRM)

November 17, 2017

Panel members:
Neil Shear (Chair), Innie Chen, Edith Guilbert, Sandra Knowles, Michele Ramien

Health Canada presenters:
Sylvie Martin, Andrew Slot

Health Canada staff observers:
Megan Bettle, David Duguay, Lucye Galand, Jenna Griffiths, Adbullah Hassen, Larissa Lefebvre, Rania Mouchantaf, Hima Murty, Conrad Pereira, Christine Perreault, Marc Poitras, Sabrina Quick

Observers:
Leah Canning (Canadian Institutes of Health Research), Robert Platt and Brandace Winquist (Drug Safety and Effectiveness Network/Canadian Network for Observational drug Effect Studies researchers), Corine Mizrahi (Project Manager, Canadian Network for Observational drug Effect Studies)

Welcome and opening remarks (Megan Bettle)
The Acting Director General of the Marketed Health Products Directorate welcomed the scientific advisory panel members. She provided context for the meeting. The risk of teratogenicity with isotretinoin use is known.  In 2005 a Scientific Advisory Panel met to make recommendations on risk mitigation measures, which were implemented over time. The Drug Safety and Effectiveness Network (DSEN) was later asked to study the effectiveness of those measures. It was found that pregnancies and adverse outcomes still occur. Thus there is a need to seek expert recommendations on what more can be done and best practices in this area.

She explained the process to be followed for the meeting, and once again thanked the panel for their time and for providing advice to Health Canada. She then handed the meeting over to the Chair of the panel.

Chair’s address (Neil Shear)
The Chair asked members and observers to introduce themselves. He reiterated the mandate of the panel, which was to provide timely scientific and medical advice on measures to mitigate the risk of birth defects associated with isotretinoin use in women of childbearing potential. The panel was asked to re-examine the effectiveness of the current Canadian pregnancy prevention measures implemented to mitigate the serious risk of birth defects associated with isotretinoin use and to make recommendations in response to questions posed by Health Canada.

He then confirmed acceptance of the terms of reference of the panel and the draft agenda for the meeting, before leading the panel members in a short verbal declaration of affiliations and interests. No conflicts of interest were declared. Before the presentations commenced, the Chair briefly reviewed the process to be followed with respect to questioning presenters.

Presentation

Isotretinoin Teratogenicity: Reassessing Canada’s Risk Minimization Strategy (Sylvie Martin and Andrew Slot)

The presentation provided background information on isotretinoin, described the current Canadian risk management plan and the pregnancy prevention program, reviewed recommendations of the 2005 Scientific Advisory Panel on isotretinoin and summarized the conclusions of the DSEN study. The presentation concluded with questions for the panel.

Issues raised by the panel, in questioning the presenter, included, but were not limited to:

• General discussion of Health Canada requirements related to risk management plans
• Availability of information on emergency contraception
• Need to consult with the Colleges of Physicians since they regulate the practice of medicine
• Changes in international experience
• Rate of pregnancies ending with major malformations
• Factors affecting reported rates of pregnancy while on isotretinoin therapy
• Types of contraception, e.g., oral / intrauterine device / injectable examined in DSEN study
• Difficulties associated with tracking compliance with contraceptive use

Deliberations on the questions posed to panel (all panel members)

In addition to the above points, the discussion covered other areas, including:

• Effect of factors such as counselling, type of contraceptive method, who is allowed to prescribe contraceptives, cost of contraceptives, compliance in different age groups etc. on pregnancy rates
• Various outcome and process measures to consider in evaluation of risk management
• Frequency and timing of pregnancy testing and access to testing
• Experience in other jurisdictions, such as in the USA
• Separation between person who prescribes retinoid, the person who prescribes the contraceptive and the dispenser
• Need for patient support programs
• Patient uptake of written risk management material
• Role of pharmacists in counselling and risk communication
• Need to engage with national professional associations such as the Society of Obstetricians and Gynaecologists of Canada (SOGC), Canadian Pharmacists Association (CPhA) and the Canadian Dermatology Association

The above list is by no means exhaustive and is intended only to give a sense of the type of issues discussed by the panel.

Final recommendations

(Note: Questions (in bold) posed by Health Canada, precede each set of recommendations)

1. What would be the criteria to consider when assessing the effectiveness of a pregnancy prevention program for isotretinoin?

Outcome measures:

• Pregnancy rate (including birth, induced abortion, miscarriage) in sexually active women who are using isotretinoin compared to sexually active age-matched women who are NOT using isotretinoin, neither of them wishing to become pregnant within the next year.
• In addition to measuring the pregnancy rate in these two cohorts, the proportion of newborns with abnormalities should be monitored.

Process measures:

• Professional adherence (including prescribers and pharmacists) to special requirements before prescribing/dispensing: e.g., discussion of teratogenic risks, two pregnancy tests before starting isotretinoin, counselling on use of two methods of contraception during use and one month after, starting isotretinoin during a menstrual period, monthly negative pregnancy test prior to isotretinoin refills
• Patient’s adherence including: contraceptive methods during use and one month after isotretinoin, two pregnancy tests before starting isotretinoin, monthly pregnancy testing

a. Is the rate of pregnancy among female isotretinoin users an optimal indicator?

Yes, the rate of pregnancy among female isotretinoin users is a good indicator for pregnancy prevention but NOT for the Risk Management Program (RMP).

• Rate of pregnancy is a very good indicator but it may not be ideal using provincial or national databases for surveillance. Rate of pregnancy would be an optimal indicator in a setting of prospective cohort studies which may not be feasible.

b. Given that no program has been effective in preventing all pregnancies, what would be a realistic threshold for determining the success of a pregnancy prevention program?

Based on data and extrapolations from the DSEN study, the annual pregnancy rate is 16-24 per 1000 female users of isotretinoin (NOTE: this is approximately a 50% decrease in the unintended pregnancy rates for females ages 15-44 years not on isotretinoin). A decrease in the pregnancy rate from current rates would indicate that the pregnancy prevention program is effective. It should be noted that comparisons can only be made if using the same methodology as in the DSEN study.

It is difficult to set a threshold because the effectiveness of pregnancy prevention programs depends on numerous factors such as:

• factors linked to the method and pregnancy testing including effectiveness of the method in typical and perfect use, accuracy of pregnancy tests
• individual factors including sexual activity, frequency of intercourse, adherence to the contraceptive method, intention to become pregnant, intention to prevent pregnancy, personal contraindications and side effects to contraceptive methods, attitude and perceived barriers to contraceptive use
• environmental factors including influence of partner, family, peers, society, access to contraceptive methods, moral norms, multiple barriers to contraceptive use
• implementation factors including complexity of the program, capacity of the program to integrate regular practice, attitudes of professionals towards the program, characteristics of professionals adopting the program, diffusion networks of the program, characteristics of organizations where the program is implemented, perceived consequences of implementing the program

Ideally, since isotretinoin is associated with a risk of major malformations, we aim to have a very sensitive decrease in the pregnancy rate. It would be recommended that all women use Tier I methods; however, we would still expect to see 1 to 8 pregnancies per 1 000 sexually active women after one year of typical use. In addition, with the actual use of contraceptive methods in Canada, rates of unintended pregnancy is estimated to be somewhere between 20% to 40%.^Footnotei

c. Should there be other criteria to consider? Please provide the rationale.

Other criteria to consider in the success of a pregnancy prevention program include rate of congenital malformations and use of Tier 1or 2 contraceptive methods (e.g., IUD, implant, progesterone injection, combined hormonal contraceptive).

• The threshold for the proportion of major malformations is very difficult to determine because it is dependent on the availability of screening and abortion services. Currently, according to data presented by DSEN, the rate of congenital malformation associated with isotretinoin among live births is approximately 9%, which is 3-4 times the current baseline risk of major malformation of 2-3% in the general population. To help decrease the proportion of major malformations associated with isotretinoin, intensification of prenatal screening in women who have used isotretinoin during pregnancy and availability of 2nd trimester induced abortion is recommended. This information could be included in the product monograph (e.g., In the event of a pregnancy, availability of ultrasound and other prenatal screening should be offered. The physician should be able to refer his/her patient to a family planning clinic or an obstetrician-gynecologist who can offer prenatal counseling and services according to patient's needs and choice.
• Use of Tier 1/2 contraceptive methods is recommended in conjunction with a Tier 3 method by women taking isotretinoin. However, there are different models across the country for contraception accessibility (e.g., in Quebec, trained RNs are authorized to prescribe oral contraceptives), and therefore it may be difficult to determine via database analysis whether a woman is using a contraceptive method (e.g., IUD).

2. Based on the discussion for question 1, is the current Canadian pregnancy prevention program effective?

Based on the information available, there is no evidence to show that the Canadian PPP is not ineffective. Processes to enhance data availability are needed to assess the current and continuing effectiveness of the Canadian PPP. The data could include: rate of pregnancy, type of contraceptive use, contraceptive use, pregnancy testing, termination rates, birth rates, and appropriateness of contraceptive use.

Opportunities could include a clearer understanding of the full complexity of isotretinoin prescribing, dispensing and the knowledge of current contraceptive knowledge. Representative national stakeholders that could be involved include: Canadian Pharmacy Association (CPhA), Canadian Dermatology Association (CDA), Society of Obstetricians and Gynecologists of Canada (SOGC), Canadian College of Family Physicians, and Canadian Medical Association (CMA).

3. Should additional measures be considered to strengthen the Canadian pregnancy prevention program?

a. Is there a need to strengthen the educational material for prescribers?

Yes. Educational material should be concise (e.g., limit information to maximum 1 double-sided page) and clear for the patient, pharmacist/dispensers, and physicians. Standard comprehension measures should apply to educational materials provided to patients (e.g., sexandu.ca). In addition, an update on contraception for prescribers and pharmacists is recommended; this would include use of emergency contraception as well as abortion options available.

It would be helpful to have evidence that the material is accessible. In addition to educational provided in the PPP there should be tools provided to the counseling physician. For example, the use of motivational strategies, or patient aids. Other suggestions for expanding the accessibility of educational programs include use of web-based module, Podcast, YouTube, social media and development of an app for patients and physicians.

b. Should there be improvement to the current informed consent form signed by the patient?

The informed consent process is crucially important for the safe initiation of isotretinoin. This consent provides an opportunity to discuss the risks and benefits of isotretinoin in a systematic fashion.

However, improvements should be made to the informed consent process to encourage compliance. Efforts should be made to ensure that the content is accessible while considering the different needs of the patient, including literacy and language gaps.

c. Should there be other measures to consider? Please provide the rationale.

• Removal of barriers to access contraception is important e.g., free contraception, direct link with a provider who can insert an IUD, having the prescriber for isotretinoin also prescribing an oral contraceptive (if appropriate).
• The information provided in the educational package should be similar among the Market Authorization Holders (MAHs). This could also include the availability of a “wallet card” to remind patients about the risk of isotretinoin in pregnancy.

4. Are there additional or alternative risk mitigation measures that could be considered to prevent pregnancy?

The recommendations are in addition to the existing measures.

• Strategies to enhance professional adherence to special requirements before prescribing isotretinoin is important to obtain favourable outcomes. In a previous Quebec study, strategies such as recall system for clinicians, use of teams in charge of improvement in standard of care, tailor-made offices, interventions targeted directly to patients and multifaceted interventions were deemed efficient in bringing health professionals to integrate prevention into their clinical practice.
• Pregnancy testing: use of pharmacist to supervise testing prior to receiving any additional isotretinoin, availability of saliva-based pregnancy test, provision of pregnancy testing kit with dispensing of isotretinoin (i.e., reimbursed by manufacturer).
• Standardized check list: for use by patient, pharmacist, dermatologist, family physician and/or OB/GYN. An App could be developed to facilitate the use of the checklist.
• Emergency contraception: should be prescribed/recommended during initial discussion with patient.
• Isotretinoin starter kit: including checklist, pregnancy test kit, medications for the first month.
• Packaging: inclusion of a large warning label on outside of packaging of isotretinoin (similar to cigarette packages).
• Funding studies on professional adherence to special requirements before prescribing isotretinoin in different parts of the country and among various healthcare professionals would possibly help identify specific barriers and propose integrated and adapted solutions.

Additional Recommendations:

• Discuss with CCHS about the inclusion of a question on isotretinoin on their sexual health survey.

Closing remarks / Adjournment (Chair)

The Chair and Health Canada thanked the members for their participation. The meeting was adjourned.