In July, 2016 a letter was sent to 14 Institutional Review Boards (IRBs) declaring that they had incorrectly approved a study of VRC01 HIV monoclonal antibody in infants at high risk of HIV infection. The study would withhold lifesaving treatment from the infants until after the experimental monoclonal
antibody was administered. Several IRBs replied that they had received the letter but only one acknowledged that the letter was being reviewed. Considering that all research studies sponsored by the US government are required to provide the contact information in the informed consents of individuals who are qualified to respond to questions or concerns, one would expect an answer in a short period of time, especially when the concern involves a significant risk to the study participants and especially when the participants are infants from a vulnerable population. After two months one would expect a definitive reply. Were the concerns taken seriously? Did the IRBs meet to discuss the concerns? Did the IRBs contact the research investigators? Were the concerns ignored? Copies of our letter of concern were also sent to NIAID, the FDA, the Presidential Bioethics Committee, the NIH Office for Human Protection, and OHRP. Only OHRP responded and is in the process of reviewing the concerns.
Below is the letter that was sent to the 14 IRBs in July.
July 14, 2016**
To: Institutional Review Boards (The names and contact information are listed in Appendix 3)
“Regarding: Approval of NIH sponsored study “PROTOCOL TITLE: IMPAACT P1112: Open-Label, Dose-Escalating, Phase I Study to Determine Safety and Pharmacokinetic Parameters of Subcutaneous (SC) VRC01, a Potent Anti-HIV Neutralizing Monoclonal Antibody in HIV-1 Exposed Infants.”
Global Strategies is a nonprofit advocacy organization founded in 1998 to encourage the implementation of HIV prevention in women and children and to ensure that relevant, scientifically sound, and ethical clinical research studies are conducted to achieve the goal of elimination of HIV.
On January 23, 2013 at a conference in Entebbe, Uganda, Arthur Ammann MD was asked to comment on a NIH proposal to conduct research in HIV exposed infants using VRC01, an experimental neutralizing monoclonal antibody to HIV. http://www.vaccineenterprise.org/content/prevention-trials-infants.
Ammann concluded that the study was premature based on lack of data on efficacy in humans, failure to compare monoclonal antibody potency to other neutralizing antibodies, and conducting experiments that had no potential benefit to a population of infants in resource poor countries raised significant ethical questions. Nevertheless plans for the study moved forward and in March, 2016 NIH announced that a 4000 patient study of VRC01 would be conducted in adults in the US, South America and sub-Saharan Africa to determine if the monoclonal antibody was safe. Additional studies were approved to concomitantly evaluate VRC01 in infants in US and South Africa to determine the pharmacokinetics and safety of the product.
Through the freedom of information act we were able to review the research protocol for adults and infants, the IRB approvals, and the informed consents. After a thorough study of these documents, we have reached the following conclusions:
- The science provided to support the use of the monoclonal antibody in infants is inadequate
- The study is being prematurely conducted before adequate safety and efficacy information in adults is available
- The IRB approval incorrectly concluded that it was ethical to conduct the study
- The IRB approval violates OHRP rules on conducting research on children
- The informed consent is inadequate
- Proceeding with the study poses significant risk to infants both in the US and in sub-Saharan Africa.
In addition to transmitting our concerns to you we have also transmitted them to NIAID, the FDA, the Presidential Bioethics Committee, the NIH Office for Human Protection, and OHRP.
Based on our concerns outlined above we request an IRB re-review of the protocol and Informed Consent as well as an additional outside independent scientific and ethical review.”
Arthur J. Ammann MD
Kerry Gough JD
** Modified from original
Additional discussion and supporting information is included in Appendix 1 and 2.
Inadequate Scientific Evidence:
VRC01 researchers in their publications, presentations, research protocol, and informed consents clearly state that VRC01 has no known efficacy in humans to prevent HIV transmission. They further state that it is unlikely that the VRC01 will ever become a useful preventative product. The scientific evidence is therefore inadequate. It is premature to embark on a study of VRC01 in infants prior to obtaining and analyzing extensive safety and efficacy studies in adults. The following has been obtained from review of documents, protocols, informed consents and presentations related to VRC01:
- “There is no human data regarding passive protection by HIV-1 monoclonal antibodies.”
- “Combinations of mABs plus ARVs are likely required for effective viral suppression.”
- “The determination of success in the study cannot be achieved… in the proposed study of infants.”
- “There are no direct benefits to you/your baby”
Inconsistencies between Individual IRBs and Incorrect IRB Approval of the Research Proposal:
- Some of the IRBs identified the proposed study as having no potential benefit to the infants while others determined that there was benefit as defined in 45 CFR 46.
- Some of the IRBs identified the studies as having minimal risk and others as greater than minimal risk. None identified the studies as having high risk. The study is in fact has identified the mothers at high risk for HIV and transmission and it follows therefore that the babies are at high risk for acquiring infection. In turn, because ARVs are withheld until the experimental agent is given, they are at high risk of acquiring fatal HIV, or lifelong chronic disease. The study is therefore prohibited under CFR 45 Part 46, Subpart D and 21 CFR 50, Subpart D: 45 CFR 46.406/21 CFR 50.53 http://www.hhs.gov/ohrp/regulations-and-policy/regulations/common-rule/index.html
- None of the IRBs required that the informed consents state that the infants would not receive immediate initiation of ARVs as recommended by WHO and US public health service guidelines for infants at high risk of acquiring HIV. (The group specifically identified for the study). (See below)
- The IRBs incorrectly identified the study as having potential benefit under the interpretation of 46 CFR 45 “Research involving greater than minimal risk and no prospect of direct benefit to individual subjects but likely to yield generalizable knowledge about the subject’s disorder or condition.” The researchers did not identify what generalizable knowledge would result from the study; the researchers acknowledged that the experimental agent will not result in a viable clinical therapeutic; they stated that a single monoclonal is unlikely to be effective; safety studies have not been conducted in adequate numbers of adults prior to initiating the study in infants; there is no scientific evidence that the product will reduce viral load to a level associated with ARVs, a criteria for all other antiretroviral products for HIV prevention. The study is therefore both unwarranted and unnecessary.
- There were inconsistent instructions by the IRBs to the investigators regarding parental signature. OHRP requires the signature of both parents for research studies in children under CFR 45 Part 46, Subpart D and 21 CFR 50, Subpart D: 45 CFR 46.406/21 CFR 50.53
Inconsistent and Incorrect Ethical Conclusions
- The population to be enrolled is deliberately selected to be at high risk for HIV transmission and infection and is precisely the population that has been identified for immediate antiretroviral prophylaxis. The study proposes to withhold standard of care treatment until after the experimental agent is administered.
- The research subjects are recruited based on lack of prenatal care, incomplete adherence tot treatment or no treatment. This is a population that is likely to be vulnerable to exploitation based on socioeconomic factors and minority status. The research subjects are being recruited/enrolled at a time when there is great sensitivity to identifying certain populations as not deserving equal protection from harm.
An Additional Concern.
The research protocol seeks to deliberately identify women who were at high risk of transmitting HIV to their infants. International USPHS guidelines state that these if it should receive immediate antiretroviral therapy. Selection of the mothers are based on enrollment criteria that suggest that they will be derived from a demographic population that the CDC has identified as being poor, underserved minority women who have not received adequate prenatal care, the diagnosis of HIV has been delayed, and/or there is poor compliance in adhering to treatment. This is a highly vulnerable population deserving of the highest standard of intervention to prevent HIV infection and not experimental treatment. Selection of this population incurs the risk of undergoing the perception of exploiting women and infants who come from substandard socioeconomic and racial demographics.
1- Recommendations USPHS to initiate ARV prophylaxis immediately after delivery to infant born to HIV infected mothers at high risk for viral transmission.
2- Recommendations WHO to initiate ARV prophylaxis immediately after delivery to infant born to HIV infected mothers at high risk for viral transmission.
3- From Discussion and Documentation
4- Definition Mothers Who Are At High Risk Of HIV Transmission to Their Infants.
1- 2015 USPHS Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States
Zidovudine, at gestational age-appropriate doses, should be initiated as close to the time of birth as possible, preferably within 6 to 12 hours of delivery (AII). Infants at higher risk of HIV acquisition, including those born to HIV-infected women who have received only intrapartum antiretroviral drugs (AI) or have not received antepartum or intrapartum antiretroviral drugs (AI) or have received antepartum antiretroviral drugs but have had suboptimal viral suppression (>1000 copies/mL) near delivery (BIII), should receive prophylaxis with zidovudine given for 6 weeks combined with three doses of nevirapine in the first week of life (i.e., at birth, 48 hours later, and 96 hours after the second dose), begun as soon after birth as possible.
Some experts recommend triple-antiretroviral prophylaxis for infants at higher risk of acquisition (as described above) although there are no data demonstrating improved efficacy for a three-drug regimen over a two-drug regimen in prevention of transmission. A decision to administer triple-antiretroviral prophylaxis should be made only in consultation with a pediatric HIV specialist, preferably before delivery, and should be accompanied by parental counseling on the potential risks (e.g., neonatal toxicity), and benefits (e.g., prevention of perinatal transmission) of this approach (BIII).
For infants born to mothers with unknown HIV status, expedited HIV testing of mothers and/or infants is recommended as soon as possible, either during labor or after birth, with immediate initiation of infant antiretroviral prophylaxis if the initial expedited test is positive (AII). If supplemental testing is negative, antiretroviral prophylaxis can be discontinued.
2- 2016 WHO Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission
ART should be initiated urgently in all pregnant and breastfeeding women, even if they are identified late in pregnancy or postpartum, because the most effective way to prevent mother-to-child HIV transmission is to reduce maternal viral load. Infants born to mothers with HIV who are at high risk of acquiring HIV should receive dual prophylaxis with AZT (twice daily) and NVP (once daily) for the first 6 weeks of life, whether they are breastfed or formula fed. Breastfed infants who are at high risk of acquiring HIV including those first identified as exposed to HIV during the postpartum period, should continue infant prophylaxis for an additional 6 weeks (total of 12 weeks of infant prophylaxis) using either AZT (twice daily) and NVP (once daily) or NVP alone.
3- From Discussion and Documentation
One of the observational studies identified by the review involved an analysis of 5,285 “high-risk” mother–infant pairs (either no or only intrapartum maternal ARV drugs or detectable maternal viral load at delivery) from eight European cohorts. Neonatal prophylaxis was administered to 88% of infants, with 24% receiving combination neonatal prophylaxis. While infant prophylaxis significantly reduced mother-to-child transmission, there was no observed difference in transmission risk between one drug and combination infant prophylaxis: the transmission rate was 18% with no infant prophylaxis, 3.4% with a single drug and 6.3% with combination prophylaxis. The second observational study was a single-arm study with a historical observational control in non-breastfeeding infants in Thailand. In this study, if mothers received less than 8 weeks of antepartum ART, the infant received AZT + 3TC + NVP for 2 weeks, followed by AZT + 3TC for an additional 2 weeks (the standard-of-care infant prophylaxis regimen is 4–6 weeks of AZT). In this study, there were no intrapartum infections in 88 mother–infant pairs.
Note: WHO declared that Cuba and eliminated perinatal HIV transmission in 2015 and Thailand in 2016.
4- WHO/UNAIDS High Risk Definition
High-risk infants are defined as those:
- Born to women with established HIV infection who have received less than four weeks of ART at the time of delivery; OR
- Born to women with established HIV infection with viral load >1000 copies/mL in the four weeks before delivery, if viral load measurement available; OR
- Born to women with incident HIV infection during pregnancy or breastfeeding; OR
- Identified for the first time during the postpartum period, with or without a negative HIV test prenatally.
Institutional Boards who were sent letter
Ann & Robert H. Lurie Children’s Hospital of Chicago
Institutional Review Board Office
225 E. Chicago Ave.
Chicago, IL 60611
Arthur Rubloff Building, 7th Floor
750 N. Lake Shore Dr.
Chicago, IL 60611
John Bixby, Ph.D.
Vice Provost for Research
Regulatory Affairs & Educational Initiatives University of Miami
Human Subject Research Office (M809)
1400 NW 10th Avenue,
Miami, FL 33136
University of California San Diego
Human Research Protections Program
9500 Gilman Drive, Mail Code 0052
La Jolla, California, 92093-0052
Casie Miller MA Senior IRB Coordinator
Erika Jorquera, Associate IRB Coordinator
Lillian Losquadro, Assistant
Grady Health System
Research Oversight Committee
Division of Medical Affairs
800 Jesse Hill Drive SE
PO Box 26118
Atlanta, GA 30303
University of Southern California
Institutional Review Board
1200 N. State Street
Los Angeles, California 90033
University of Florida
Institutional Review Board
580 W. 8th St.,
Jacksonville, FL 32209
Bronx Lebanon/Albert Einstein
Institutional Review Board
Bronx Lebanon Hospital Center
1650 Grand Concourse
Bronx, NY 10457
The Committees for the Protection of Human Subjects
Children’s Hospital of Philadelphia
3400 Spruce St.
Philadelphia, PA 19104
Daniel Clemens MD
University of California Los Angeles
11000 Kinross Ave suite 211
Los Angeles, CA 90095
Office of Human Subjects Research
1620 McElderly Street
Reed Hall Suite B 130
Baltimore, MD 21205
Colorado Multiple Institutional Review Board
University of Colorado
Anschutz Medical Campus
13001 E. 17th Pl.
Aurora, CO 80045
Robin Smith MBA
Institutional Review Board Manager
1600 S. Andrews Ave., Fort Lauderdale, FL 33316