The clinical research process involves a progression of studies that build upon one another. These studies are designed to answer specific research questions. For pharmaceutical product development studies, this includes evaluating dose-response, safety, efficacy and acceptability. Proof-of-concept clinical trials, also known as test-of-concept studies, play an essential role in the product discovery and development process. 

Proof-of-concept (or PoC) studies are typically early-stage clinical trials conducted to understand whether an investigational product elicits a pathophysiologic signal, that is, does it produce the expected response in individuals. These studies usually include a placebo arm (i.e., an inert treatment or substance that has no known effects) to determine whether the investigational product has a real physiological effect. The effect's magnitude is evaluated to determine a product's potential for further studies, including dose-escalation and efficacy trials. Put simply, the ultimate research question to answer in a proof-of-concept study is whether the concept or idea is worth pursuing further.

Mark Marzinke
Dr. Mark Marzinke

“It is important to note proof-of-concept studies are not meant to demonstrate efficacy within a population, nor signal the scale-up of a product for deployment,” said Dr. Mark Marzinke, member of the HPTN Laboratory Center Pharmacology Core and director of the Clinical Pharmacology Analytical Laboratory at the Johns Hopkins School of Medicine in Baltimore. “Rather, these studies are geared to assess the potential viability of an investigational product to achieve sufficient biological activity to warrant further investigation.”

Additional goals of proof-of-concept studies often include: (1) extending the safety profile of a new product (e.g., evaluating a product over multiple doses or an extended period of exposure); (2) assessing clinical activity (e.g., does it prevent HIV); (3) determining the optimal effective dose; and (4) helping us understand how a particular product or class of products may be working (e.g., how it may interact with our immune systems or with its target, like HIV).


Many PoC study challenges are comparable to those found in other clinical research studies. These may include identifying the appropriate study population, barriers to recruitment and retention, and determining the optimum protocol design. Important statistical considerations are a critical part of the process. PoC studies are traditionally not performed in large populations; therefore, understanding how to measure and interpret the potential study product effect in a limited sample size is essential.

Deborah Donnell
Dr. Deborah Donnell

“The design of proof-of-concept studies is always quite challenging because you want to get enough evidence to discern whether the idea has merit, but you don’t need regulatory level proof of efficacy,” said Dr. Deborah Donnell, principal investigator of the HPTN Statistical and Data Management Center, principal staff scientist in the Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center and affiliate associate professor, Department of Global Health, the University of Washington in Seattle.

Educating communities and potential study participants regarding PoC studies can raise a unique challenge. With many pharmaceutical product development studies, there is an expectation that it will eventually be available to the public if found to be safe and effective. However, for some PoC studies, even if the product is safe and effective, there may be no plans to advance towards commercialization. Reasons may include: the product is not easily scalable in its current form, general administration is not feasible, or various other product-related or logistical reasons such as the need for a cold-chain supply.  According to Robert Bucklew, outreach coordinator for the Case Western Reserve University/University Hospitals AIDS Clinical Trials Unit in Cleveland, not commercializing an investigational product – even when there was never an expectation to do so – can be interpreted by the community as a failure. Therefore, ongoing community engagement and education is necessary to maintain public trust and investment in the research process.

Bob Bucklew
Robert Bucklew

“Study site staff need to include the site’s Community Advisory Board and other community engagement partners in developing messaging about proof-of-concept trials,” said Bucklew. “Inclusion will hopefully help provide language that is understandable, thorough, and addresses possible community misperceptions about the underlying purpose of the trial as well as explaining study results and next steps."

AMP Studies
AMP logo
HVTN 704/HPTN 085 logo

In 2016, the HIV Prevention Trials Network (HPTN) and the HIV Vaccine Trials Network (HVTN) initiated HVTN 703/HPTN 081 and HVTN 704/HPTN 085, also known as Antibody Mediated Prevention (AMP), two proof-of-concept clinical trials to evaluate the safety and efficacy of VRC01, a broadly neutralizing monoclonal antibody (bnAb). The AMP studies are the first to assess whether bnAbs effectively reduce the acquisition of HIV-1 infection among at-risk populations. HVTN 703/HPTN 081 enrolled about 1,900 adult women in sub-Saharan Africa who are vulnerable to HIV infection. HVTN 704/HPTN 085 was conducted in the U.S., Brazil, Peru, and Switzerland, and enrolled approximately 2,700 cisgender men or transgender people who have sex with men.

Nyaradzo Mgodi
Dr. Nyaradzo Mavis Mgodi

“We set out to do these test-of-concept AMP studies to establish life-changing concepts – similar to how AZT revolutionized the anti-retroviral field 20 years ago – that could fast-track HIV vaccine development and expand the HIV prevention toolbox, ” said Dr. Nyaradzo Mavis Mgodi, protocol co-chairperson for HVTN 703/HPTN 081 study, member of the HPTN Executive Committee and a scientific reviewer for the Medical Research Council of Zimbabwe. “By exploring an established concept of antibody prevention for infectious disease, and working to extend that concept to HIV, we hope to advance the HIV prevention field further and faster.”

AMP logo
HVTN 703/HPTN 081 logo

The primary results of these studies are expected to be released later this year. AMP researchers have no plans to seek licensure for public use of the VRC01 antibody. Instead, researchers will use what is learned from these proof of concept studies to design studies to evaluate newer antibodies including combinations of antibodies.  


In the absence of an effective HIV vaccine, researchers continue investigating new and innovative prevention approaches to meet diverse communities' needs worldwide. These approaches include using PoC studies to evaluate new pharmaceutical strategies and identify the most promising candidates for HIV prevention.