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A Delicate Balance: Accelerated Approval and Postmarketing Commitments

tagline 2009 April


Research presentation poster by Tracy Swan and Lei Chou; winner of a Chairman’s Choice Award at the 2008 HIV DART conference “Frontiers in Drug Development for Antiretroviral Therapies.” The complete text is available online.


Populations in Preapproval Studies and Postmarketing Commitments, 2005–2008

Aptivus (tipranavir, TPV), approved on June 22, 2005
Women12% female
HBV/HCV coinfection~10% coinfected
Renal/hepatic impairmentHas not been studied in people with moderate
or severe hepatic impairment or severe hepatic
impairment.
Renal clearance is negligible, therefore difference in
clearance not expected or studied in persons with renal
impairment
Postmarketing
commitment
Released from: methadone/buprenorphine interaction
study; 48-week prospective observational diversity
cohort study stratified by race and gender to assess
efficacy and safety including potential risk parameters
such as CD4 count and coinfection
Pending: drug-drug interaction study of PEG-IFN alfa
2a and TPV/ritonavir; pharmacokinetics (PK) in HIVnegative
persons with Child-Pugh class B liver disease;
formal QT prolongation study
Intelence (etravirine), approved on January 18, 2008
Women~10%
HBV/HCV coinfection12.4%
Renal/hepatic impairmentStudied in people with mild and moderate hepatic
impairment
Renal clearance is negligible, therefore difference in
clearance not expected or studied in persons with renal
impairment
Postmarketing
commitment
48-week study of ARV-experienced females to
elucidate potential differences in safety and efficacy
Isentress (raltegravir), approved on October 12, 2007
WomenARV experienced: ~12%; ARV naive: 20%
HBV/HCV coinfectionARV experienced: HB V coinfected 6%; HC V coinfected
~9%; HBV/HCV <1%; ARV naive: 7% overall
Renal/hepatic impairmentStudied in people with moderate hepatic impairment and
severe renal impairment
Postmarketing
commitment
48-week nonrandomized open-label, single-arm study
in 200 people—at least 50% African American and at
least 25% female—to characterize efficacy and safety of
raltegravir in a population that closely reflects the U.S.
HIV-infected population
Prezista (darunavir, DRV), approved on June 23, 2006
WomenARV experienced: ~11%; ARV naive: 30%
HBV/HCV coinfectionARV experienced: Yes; number unspecified; ARV naive:
~13%
Renal/hepatic impairmentNot studied in people with hepatic impairment; studied
in people with moderate renal impairment
Postmarketing
commitment
Conduct study of DRV/ritonavir in treatmentexperienced
female patients to elucidate differences in
efficacy and safety; drug-drug interaction study with
buprenorphine/nalaxone
Selzentry (maraviroc, MVC), approved on August 6, 2007
WomenARV experienced: ~11%; ARV naive: 29%
HBV/HCV coinfectionARV experienced: 6% HB V coinfected; 6% HC V
coinfected; ARV naive: unknown
Renal/hepatic impairmentNot specifically studied in renal impairment or
sufficiently studied in hepatic impairment
Postmarketing
commitment
Study in coinfected people including people with
Child-Pugh class C; assess effect of renal impairment
on maraviroc PK at a dose of 150 mg combined with
a boosted protease inhibitor (in people with mild to
moderate renal impairment) and 300 mg alone (in
people with severe renal impairment and on dialysis)


Ongoing Underrepresentation

The underrepresentation of women, people of color, and drug users in clinical trials for AIDS/HIV has been an ongoing concern for HIV treatment activists, who routinely push the pharmaceutical industry and the public research networks to enroll trial populations that are representative of the actual HIV demographics in the United States. According to recent Centers for Disease Control and Prevention data on U.S. HIV prevalence, women constitute approximately 25% of those with HIV infection; African Americans, a staggering 46%; Hispanics, 17%; and injection drug users, 18%. All of these populations are typically underenrolled in HIV clinical trials.

Swan and Chou’s presentation focuses on the clinical trials of five recently approved antiretroviral (ARV) drugs and highlights the sharp contrast between the demographics of the trials’ participants and the demographics of the U.S. epidemic. Their study notes that “insufficient enrollment of special populations—an umbrella term for women, people of color, and people with common comorbid conditions, such as renal impairment and viral hepatitis—has led FDA to request postmarketing commitments (PMCs) for five recently approved antiretroviral agents.”

The authors conclude with these key points:

  • Preapproval trials can address concerns usually dealt with in postmarketing commitments, through diverse enrollment and a more thorough portfolio of pharmacokinetic and drug-to-drug interaction studies.
     
  • Regulators need larger, more tempting carrots and sharper sticks to prompt more thorough premarketing studies, and prompt initiation of postmarketing commitments.