Summary Basis of Decision for Pifeltro
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Pifeltro is located below.
Recent Activity for Pifeltro
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
The following table describes post-authorization activity for Pifeltro, a product which contains the medicinal ingredient doravirine. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Drug Identification Number (DIN):
DIN 02481545 – 100 mg doravirine, tablet, oral administration
Post-Authorization Activity Table (PAAT)
|Activity/submission type, control number
|Decision and date
|Summary of activities
|SNDS # 265860
|Issued NOC 2022-12-14
|Submission filed as a Level I – Supplement to update the mock-up bottle label. The submission was reviewed and considered acceptable, and an NOC was issued.
|SNDS # 223943
|Issued NOC 2019-12-06
|Submission filed as a Level I – Supplement to update the PM with new safety and efficacy data from studies Drive-Forward, Drive-Ahead, and Drive-Shift. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
|Drug product (DIN 02481545) market notification
|Date of first sale: 2018-11-14
|The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
|NDS # 211293
|Issued NOC 2018-10-12
|NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Pifeltro
Date SBD issued: 2019-03-11
The following information relates to the New Drug Submission for Pifeltro.
100 mg, tablet, oral
Drug Identification Number (DIN): 02481545
Merck Canada Inc.
New Drug Submission Control Number: 211293
On October 12, 2018, Health Canada issued a Notice of Compliance to Merck Canada Inc. for the drug product Pifeltro.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-harm-uncertainty profile of Pifeltro is favourable in combination with other antiretroviral medicinal products, for the treatment of adults infected with human immunodeficiency virus-1 (HIV-1) without past or present evidence of viral resistance to doravirine.
1 What was approved?
Pifeltro, a non-nucleoside reverse transcriptase inhibitor (NNRTI), was authorized, in combination with other antiretroviral medicinal products, for the treatment of adults infected with human immunodeficiency virus-1 (HIV-1) without past or present evidence of viral resistance to doravirine.
The safety and efficacy of Pifeltro have not been established in pediatric patients (<18 years of age), and data regarding use in geriatric patients (≥65 years of age) is limited.
Pifeltro is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. Additionally, Pifeltro is contraindicated with drugs that are strong cytochrome P450 (CYP) 3A enzyme inducers. Concurrent use may cause significant decreases in doravirine plasma concentrations, which may decrease the effectiveness of Pifeltro. These drugs include, but are not limited to:
- The anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, and phenytoin
- The androgen receptor inhibitor enzalutamide
- The antimycobacterials rifampin and rifapentine (rifapentine not marketed in Canada)
- The cytotoxic agent mitotane
- St. John's wort (Hypericum perforatum).
Pifeltro was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Pifeltro (100 mg doravirine) is presented as tablets. In addition to the medicinal ingredient, the tablets contain carnauba wax, colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The film coating consists of hypromellose, lactose monohydrate, titanium dioxide, and triacetin.
Additional information may be found in the Pifeltro Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Pifeltro approved?
Health Canada considers that the benefit-harm-uncertainty profile of Pifeltro is favourable, in combination with other antiretroviral medicinal products, for the treatment of adults infected with human immunodeficiency virus-1 (HIV-1) without past or present evidence of viral resistance to doravirine.
HIV-1 infection is a life-threatening disease with a cumulative total of 78,511 cases reported to the Public Health Agency of Canada since reporting began in Canada in 1985. The recommended initial treatment regimen for ART-naïve HIV-1 patients consists of two nucleos(t)ide reverse transcriptase inhibitors (N[t]RTI) combined with either a non-nucleoside reverse transcriptase inhibitor (NNRTI), a boosted protease inhibitor (PI), or an integrase strand-transfer inhibitor (INSTI).
Doravirine, the medicinal ingredient in Pifeltro, is a pyridinone NNRTI. Doravirine inhibits HIV-1 replication by non-competitive inhibition of the HIV-1 reverse transcriptase. Pifeltro has been shown to be efficacious in combination with other antiretroviral medicinal products, in adult patients with HIV-1 without past or present evidence of viral resistance to doravirine.
The market authorization was based primarily on two pivotal Phase III clinical trials: DRIVE-FORWARD and DRIVE-AHEAD. Both trials were randomized, double-blind, and active-controlled, and both demonstrated the non-inferiority of Pifeltro in ART-naïve adult patients.
The DRIVE-FORWARD trial compared Pifeltro (100 mg) to darunavir/ritonavir (800 mg/100 mg) in adult patients; each in combination with either emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF), or abacavir (ABC)/lamivudine (3TC). The nucleoside reverse transcriptase inhibitor (NRTI) background therapy (either FTC/TDF or ABC/3TC) was chosen by the clinical investigator. Approximately 50 patients in each treatment arm received ABC/3TC as the background therapy, and the remaining patients received FTC/TDF. Patients were randomized in a 1:1 ratio to one of these two treatment groups, and took their assigned treatment once daily for 48 weeks.
The primary endpoint to assess efficacy was the percentage of patients with <50 copies/mL of HIV-1 ribonucleic acid (RNA) at Week 48, measured using the FDA Snapshot method.
Results indicated that the efficacy of Pifeltro combined with two NRTIs (either FTC/TDF or ABC/3TC) is non-inferior to the efficacy of the comparator, darunavir/ritonavir combined with two NRTIs. Among the patients receiving Pifeltro with two NRTIs, 84% had <50 copies/mL of HIV-1 RNA at Week 48, versus 80% of patients receiving the comparator treatment. Additionally, similar efficacy was detected in patients within the same treatment group, regardless of which NRTI background therapy was administered.
The DRIVE-AHEAD trial compared a fixed dose of Pifeltro/TDF/3TC against a fixed dose of efavirenz (EFV)/FTC/TDF. Patients were randomized in a 1:1 ratio to receive one of these two treatments, and took their assigned treatment once daily for 48 weeks.
The primary endpoint to assess efficacy was the percentage of patients with <50 copies/mL of HIV-1 RNA at Week 48, measured using the FDA Snapshot method.
Results indicated that the efficacy of Pifeltro/TDF/3TC was non-inferior to the efficacy of the comparator, EFV/FTC/TDF, after 48 weeks of treatment. Among the patients receiving Pifeltro/TDF/3TC, 84% had <50 copies/mL of HIV-1 RNA, versus 81% of patients receiving the comparator treatment.
Adverse events associated with NNRTIs include rash and neuropsychiatric events, particularly dizziness and sleep disorders, and were observed in both pivotal trials. These occurred at similar frequencies between the two treatment groups in DRIVE-FORWARD. In DRIVE-AHEAD, these occurred less frequently in patients receiving Pifeltro/TDF/3TC.
Plasma concentrations of various lipids were monitored for changes from baseline levels, as antiretroviral therapy (ART) can cause them to increase. Data from both pivotal trials indicated that Pifeltro has a neutral lipid profile relative to the comparator treatments.
In both pivotal trials, elevated bilirubin (Grade 1 or Grade 2) was detected more frequently in patients in the group receiving Pifeltro. Elevation was transient in most cases, and the majority of patients with Grade 2 elevation at Week 48 also had elevated bilirubin at screening or study initiation.
Rates of adverse events, serious adverse events, and discontinuations are addressed in the Clinical Safety section. Overall, the adverse event data indicate that Pifeltro has an acceptable safety and tolerability profile.
A Risk Management Plan (RMP) for Pifeltro was submitted by Merck Canada Inc. to Health Canada. The RMP was considered to be acceptable upon review, with revisions required within 90 days. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Pifeltro Product Monograph meet the necessary regulatory labelling, plain language and design element requirements. A Look-alike Sound-alike brand name assessment was performed and the proposed name Pifeltro was accepted.
Overall, the therapeutic benefits of Pifeltro therapy seen in the pivotal studies are non-inferior to the comparators, and are considered to outweigh the potential risks. Pifeltro has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Pifeltro Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Pifeltro?
Submission Milestones: Pifeltro
|Screening Deficiency Notice issued:
|Screening Acceptance Letter issued:
|Quality Evaluation complete:
|Clinical Evaluation complete:
|Review of Risk Management Plan complete:
|Labelling Review complete, including Look-alike Sound-alike brand name assessment:
|Notice of Compliance issued by Director General, Therapeutic Products Directorate:
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision
Doravirine, the medicinal ingredient in Pifeltro, is a non-nucleoside reverse transcriptase inhibitor (NNRTI). It interferes with viral replication through non-competitive inhibition of the human immunodeficiency virus-1 (HIV-1) reverse transcriptase enzyme.
The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of Pifeltro have been well-characterized in patients and healthy volunteers. Additionally, doravirine did not prolong the QT interval following a 1,200 mg dose, which provides four times the peak concentration of the maximum approved dose. Overall the pharmacokinetic data support use of Pifeltro for the approved indication.
The antiviral activity of doravirine was initially observed in vitro, against wild-type laboratory strains of HIV-1 as well as primary isolates. The resistance profile of doravirine was also analyzed in vitro, with a wide range of NNRTI-associated mutant viruses. The resistance profile of doravirine was determined to be superior to that of efavirenz, and similar to those of etravirine and rilpivirine. Most mutants displaying a >10-fold resistance to doravirine required multiple mutations.
For further details, please refer to the Pifeltro Product Monograph, approved by Health Canada and available through the Drug Product Database.
The non-inferiority of Pifeltro, used with other antiretroviral agents, was demonstrated mainly through two Phase III pivotal trials: DRIVE-FORWARD and DRIVE-AHEAD. Each trial tested a combination of Pifeltro and two nucleoside reverse transcriptase inhibitors (NRTIs) against a comparator treatment combining multiple antiretroviral agents with established efficacy. Both trials were randomized, double-blind, and active-controlled.
The DRIVE-FORWARD trial compared Pifeltro (100 mg) to darunavir/ritonavir (800 mg/100 mg); each combined with either tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), or abacavir (ABC)/lamivudine (3TC). The NRTI background therapy (TDF/FTC or ABC/3TC) administered to each patient was determined by the investigator. This trial included 766 treatment-naïve adult patients randomized in a 1:1 ratio, resulting in 383 patients in each treatment group. Approximately 50 patients in each treatment arm received ABC/3TC as background therapy, while the remaining patients received TDF/FTC. Patients took their assigned treatment orally once per day, for 48 weeks.
The primary endpoint used to assess efficacy was the percentage of patients who had <50 copies/mL of HIV-1 RNA at Week 48, measured by the Food and Drug Administration (FDA) Snapshot method. At Week 48, this was achieved by 84% of patients receiving Pifeltro and 80% of patients receiving the comparator. Within each treatment group, similar efficacy was observed between patients regardless of the background therapy.
One patient receiving Pifeltro (out of 383) developed genotypic and phenotypic resistance during the course of the study. This frequency, 0.3%, is much lower than those recently reported for other NNRTIs. These observations are consistent with results of in vitro studies indicating that a higher threshold must be met to develop resistance to Pifeltro, compared to other NNRTIs.
The DRIVE-AHEAD trial compared fixed-dose combinations of Pifeltro/TDF/3TC and efavirenz (EFV)/TDF/FTC. This trial included 728 treatment-naïve adult patients randomized in a 1:1 ratio, resulting in 364 patients in each treatment group.
The primary efficacy endpoint in DRIVE-AHEAD was the percentage of patients who had <50 copies/mL of HIV-1 RNA at Week 48, measured by the FDA Snapshot method. This was achieved by 84% of patients treated with Pifeltro/TDF/3TC, and by 81% of patients receiving the comparator treatment.
Analyses of isolates from the patients revealed that seven individuals treated with Pifeltro/TDF/3TC had mutations associated with resistance to Pifeltro. Six patients had genotypic and phenotypic resistance, and one patient had only genotypic resistance. Six of the seven patients also had mutations associated with resistance to 3TC and/or TDF. Resistance was mainly acquired through a substitution in the amino acid valine at position 106 (V106) of the HIV-1 reverse transcriptase enzyme, along with at least one other mutation. These observations support the in vitro data indicating that multiple mutations are required for high-level resistance to Pifeltro.
Collectively, the outcomes of the two pivotal trials demonstrate that Pifeltro, combined with other antiretroviral agents, is non-inferior to several comparator combination treatments with established efficacy. Both trials also provide evidence that multiple mutations are required to develop resistance to Pifeltro.
The New Drug Submission for Pifeltro was filed by the sponsor with the following indication, which was approved by Health Canada:
Pifeltro (doravirine) is indicated, in combination with other antiretroviral medicinal products, for the treatment of adults infected with HIV-1 without past or present evidence of viral resistance to doravirine.
For more information, refer to the Pifeltro Product Monograph, approved by Health Canada and available through the Drug Product Database.
The clinical safety of Pifeltro was established primarily through the two pivotal trials, DRIVE-FORWARD and DRIVE-AHEAD. The designs of both trials are described in the Clinical Efficacy section.
Pifeltro was generally well-tolerated in the DRIVE-FORWARD study, with few discontinuations related to adverse events and a low frequency of serious adverse events (5.0%). The percentage of patients who experienced drug-related adverse events was similar between the two treatment groups (30.5% of patients receiving Pifeltro, and 32.1% of patients receiving darunavir/ritonavir). Four patients receiving Pifeltro and eight patients receiving darunavir/ritonavir discontinued treatment due to drug-related adverse events. Discontinuations in the latter group were primarily due to gastrointestinal adverse events, which are known effects of ritonavir. One patient in the group receiving Pifeltro died during the trial. This event was determined to be unrelated to the treatment.
Rash and neuropsychiatric adverse events (particularly dizziness and sleep disorders) are associated with other NNRTIs, and were observed in this study at similar frequencies between the two treatment groups. Two discontinuations were due to rash, and none were due to neuropsychiatric events.
Plasma concentrations of various lipids were monitored, as antiretroviral therapy (ART) can cause lipid levels to increase. Measurements of low-density-lipoprotein cholesterol (LDL-C), non-high-density-lipoprotein cholesterol (non-HDL-C), total cholesterol, triglycerides, and HDL-C indicate that Pifeltro has a neutral lipid profile compared with darunavir/ritonavir.
Elevated bilirubin (Grade 1 or 2) was observed in 6.6% of patients receiving Pifeltro, and in 1.4% of patients receiving darunavir/ritonavir. Elevation was transient in most cases, and the majority of patients with Grade 2 elevation at Week 48 also had elevated bilirubin at screening or trial initiation. No cases of elevated bilirubin were associated with clinically significant adverse events, and no patients met the criteria for drug-induced liver injury (DILI) during this study.
Consistent with the outcomes of the DRIVE-FORWARD study, Pifeltro was well-tolerated in the DRIVE-AHEAD study. Similar frequencies of serious adverse events were observed in both treatment groups. Patients in the group receiving Pifeltro/TDF/3TC experienced fewer drug-related adverse events (31.0% vs. 62.9% of patients receiving the comparator), fewer discontinuations due to adverse events (3.0% vs. 6.6%), and fewer discontinuations due to drug-related adverse events (2.2% vs. 5.8%). These were driven mainly by rash and neuropsychiatric events, which are known effects of NNRTIs. Ten patients receiving the comparator treatment discontinued due to rash. There were no discontinuations in the Pifeltro/TDF/3TC treatment group.
A larger proportion of patients receiving Pifeltro/TDF/3TC had elevated bilirubin (Grade 1 or 2) at Week 48, compared with patients receiving the comparator treatment. Most cases observed were transient, and the majority of patients with Grade 2 elevation at Week 48 already had elevated bilirubin at screening or study initiation.
Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Pifeltro, and to promote its safe and effective use. Overall, the benefit-harm-uncertainty profile of Pifeltro is favourable for the approved indication. For more information, refer to the Pifeltro Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The antiviral activity of doravirine, the medicinal ingredient in Pifeltro, was first observed in in vitro studies against various clinical isolates and wild-type laboratory strains of HIV-1. The activity of doravirine was also evaluated against a range of viral strains carrying mutations associated with resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs). The resistance profile of doravirine was similar to those of etravirine and rilpivarine, and superior to the profile of efavirenz. Most mutants with >10-fold higher resistance to doravirine had multiple mutations.
Safety pharmacology and repeat-dose toxicology studies with clinically relevant doses of doravirine did not reveal any significant safety concerns or target organs of toxicity. Doravirine was also non-genotoxic in in vitro and in vivo assays, and showed no signs of carcinogenic potential in rats and transgenic mice.
Doravirine had no effects on reproductive, developmental, or behavioural parameters in rats and rabbits at doses yielding approximately seven times the exposure of the recommended human dose. However, non-clinical data indicates that doravirine can cross the placental barrier in gestating rats and rabbits, and it was excreted into the milk of lactating rats. Pregnant women are therefore advised not to take Pifeltro unless the potential benefits of the treatment exceed the potential risks to the fetus. Additionally, mothers positive for HIV-1 should not breastfeed due to the potential for transmission of HIV-1 to the child.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Pifeltro Product Monograph. Considering the intended use of Pifeltro, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Pifeltro Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Pifeltro has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Proposed limits of drug-related impurities have been adequately qualified through toxicological studies.
Based on the stability data submitted, the proposed shelf life of 30 months is acceptable when the drug product is stored at room temperature (15ºC to 30ºC).
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. Lactose monohydrate, an excipient in Pifeltro tablets, is of animal origin. Lactose monohydrate used in the production of Pifeltro is sourced from healthy animals under the same conditions as milk which is intended for human consumption. It is not considered a risk for bovine spongiform encephalopathy or transmissible spongiform encephalopathy (BSE or TSE), and complies with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMA/410/01).