Adaptive Trial Design 1: An Overview

Adaptive Trial Design 1: An Overview

Adaptive trial design refers to a clinical trial methodology that allows trial design modifications to be made after patients have been enrolled in a study, without compromising the scientific method. In order to maintain the integrity of the trial, these modifications should be clearly defined in the protocol.

When designed well, an adaptive trial empowers sponsors to respond to data collected during the trial. This is achieved by re-focusing the trial in a way that maximises the impact of each subject’s contribution. Examples of adaptive trial designs include dropping a treatment arm, modifying the sample size, balancing treatment assignments using adaptive randomisation or simply stopping a study early for success or failure.

In a standard trial, safety and efficacy data are collected and reviewed by a monitoring board during scheduled interim analyses. However, aside from stopping a study for safety reasons, very little can be done in response to that data. Often, a whole new study must be designed to further investigate key trial findings.

In an adaptive trial, the sponsor might have the option of responding to interim safety and efficacy data in a number of different ways, including narrowing the trial focus or increasing the patient population. An example of narrowing the trial focus includes removal of one or more of the treatment arms based on predetermined futility rules. Alternatively, if the data available at the time of the review do not allow for a clear decision between utility and futility, it might be decided to expand the enrolment of patients on one or more treatment arms beyond the initially targeted sample size.

Another example of adaptive design is the response-adaptive. In a response-adaptive setting, patients are randomised to treatment arms based on the response to treatment of previous patients. In a response adaptive trial, real-time safety and efficacy data can be incorporated into the randomisation strategy in order to influence subsequent adaptive randomisation decisions on a patient-by-patient basis. An example of response-adaptive randomisation is “play-the-winner”, which assigns patients to treatment arms that have resulted in fewer adverse events or better efficacy.

As these examples demonstrate, the adaptive design concept can be utilised in a number of different ways to increase trial flexibility. In a well-designed adaptive trial, that flexibility can result in lower drug development costs, reduced time to market and improved patient safety. Cost reduction is achieved by stopping unsuccessful trials earlier, identifying successful trials sooner, dropping unnecessary treatment arms or determining effective dose regimens faster.

Time to market can be accelerated by identifying successful trials sooner and reducing, or removing entirely, the lead time between trial phases, especially Phases II and III. Patient safety is improved because adaptive trials tend to reduce exposure to unsuccessful treatment arms (which are dropped early), and increase access to effective treatment arms (via response adaptive randomisation).

Article written by: Eva Miller, Manager of Biostatistical Services, Stephane Deleger, West Coast Business Development Manager, and Jim Murphy, Vice President of Business Development and Marketing at Interactive Clinical Technologies, Inc (ICTI)

The authors can be contacted at info@icti-almac.com

Full paper can be accessed at: http://www.pharmaceutical-int.com/article/implementing-and-managing-adaptive-designs-for-clinical-trials.html

Perceptive survey highlights growing interest in adaptive trial designs

Perceptive survey highlights growing interest in adaptive trial designs

DATE: 26 April 2011

SOURCE: Outsourcing-Pharma.com

AUTHOR: Alexandria Pesic

http://www.outsourcing-pharma.com/Clinical-Development/Perceptive-survey-highlights-growing-interest-in-adaptive-tria… 

Perceptive Informatics, the eClinical Solutions provider and Parexel subsidiary, has released the results of a global survey which shows a growing interest in the implementation of adaptive trial designs. Entitled “Implementing Bayesian Response Adaptive Trials,” the survey was conducted during a recent webinar presented by Perceptive and UK-based science and technology consultants, Tessella. It canvassed the opinion of more than 300 industry professionals representing a broad range of clinical, statistical and regulatory functions. The results revealed that 80 per cent of respondents were considering implementing some type of adaptive design in the next twelve months. Of that 80 per cent, 76 per cent were considering designs that drop treatment arms at fixed interim analyses. However, only 24 per cent of respondents said they expected to implement designs that regularly adjust the randomisation ratio throughout the study – a technique known as response adaptive design.

Commenting on the findings, Damian McEntergart, senior director of statistics and product support at Perceptive, said: “Following the FDA draft guidance on adaptive trials, increasing implementation of these designs has helped to alleviate regulatory acceptance concerns within the industry.” An important requirement for adaptive trials is the ability to include more dose levels in Phase II dose-finding studies without significantly increasing the number of study participants or the length of timelines.”

Workshop on Interpreting and communicating biomedical HIV prevention research trial results

The New HIV Vaccine and Microbicide Advocacy Society, Lagos announces a workshop on Interpreting and communicating biomedical HIV prevention research trial results

 

Date : February 22nd to 24th, 2011
Venue: Abuja, Nigeria

Rationale:
There are increasing numbers of biomedical HIV prevention research being planned, and ongoing. The outcome of these global research efforts have implications the national HIV prevention programming in Nigeria and the various HIV prevention work we conduct in the community. Nigeria will also be engaged in various biomedical HIV prevention research efforts in the near future. This training will address the capacity needs of those who work at the grassroot on how to interprete the various biomedical HIV prevention research trial results and how the results can be effectlively communicated to members of their community in a timely and useable fashion.
Workshop Objectives:
At the end of the workshop, participants will be able to:
– Understand the rationale for biomedical HIV prevention research

– How biomedical HIV prevention researches are designed

– Ethical considerations in the design and impementation of biomedical HIV prevention research

– Statistical considerations in biomedical HIV prevention research

– How to interprete the published results of clinical trials

– How to communicated and use the results of these trials in the community
Workshop Contents:

– Basic definitions of New HIV prevention technologies (NPT)

– The need for NPT researches

– Overview of NPT researches

– Actors in the field of NPT research

– State of NPT research

– Ethics of NPT research

– Analysis of NPT clinical trial results

– Communicating results and use for designing programmes

– Next steps
The workshop is designed to be participatory with the use of multiple tools to facilitate understanding of research concepts and statistics. Hands-on experience in designing plans for community education on biomedical HIV prevention trials will be gained by doing exercises, and working in small groups throughout the workshop. The participant groups will present the results of their exercises and group discussions during the workshop.

Eligibility:
The course is designed for Members of CSOs, community liasions, and field workers affiliated to reseach sites. Interested journalists, ethics committee members are also welcome.

 

Faculty:
This workshop will be taught by experts from the New HIV Vaccine and Microbicide Advocacy Society using tools that have been pretested.

 

Application procedures & Submission:

Space limited to only 30 applicants.

For further information, comments and reservation please contact Aisha Abdullahi <aishatuabdullahi@yahoo.com>; Florita Durueke <chichiflorita@yahoo.com>; Augusta Obyamiziam obyamuziam@yahoo.com

One antiretroviral pill a day may keep HIV infection away: call for action NHVMAS outlines potential next steps for the Nigerian Community

The result of the iPrEx study anounced on the 23rd of November 2010 brings lots of new excitement and hope to the field of HIV prevention. The study showed that the use of one antiretroviral pill– Truvada – consistently  every day has the potential of
reducing the risk of contracting HIV infection by up to 92-95%.
The study was conducted amongst 2,499 MSM study participants recruited in Brazil, Ecuador, Peru, South Africa, Thailand and USA. The study involved having some of these participants take Truvada every day while other participants took a pill that
looks like Truvada but was not active like Truvada (a placebo). All study participants visted the clinic every month and got tested to check for HIV infection, proper kidney function, and possibility of HIV drug resistance. Study participants were also asked to report on their daily drug use. The pills not used were counted at every study visit. The pills taken by each study participants was calculated by substracting the number of pills left from the number of pills dispensed. Also, in a few participants, blood was taken to examine if there was traces of the drug in their blood as evidence of taking the drug. Analysis of the result showed that:
(i) based on the self report, Truvada is 43.8% effective in prevention new HIV infection among MSMs who engage in sex
(ii) the drug was more protective in study participants who took the drug regularly.For those who took the drug at least 50% of the time based on pill counting, the drug was able to reduce the risk of HIV infection during sex by 50.2%. For those who used the drug at least 90% of the time, the drug was able to reduce the risk of HIV infection during sex by 72.8%.
(iii) having detectable levels of Truvada in the blood was associated with reduced chances of contracting HIV infection when on daily drug regimen. It does not completely eliminate the chances though
(iii) if drug adherence were to be 100%, the drug can possible confera 92-95% protection from HIV infection.
(iv) The drug was found safe with mild side effect. No HIV negative study participant who the trial developed HIV resistance. Neither did any of the study participants who seroconverted. The two study participants who developed resistance appear to have been infected with HIV before their study enrollment.

What does this mean to us as Nigerians?
1. Call to the National Agency for Food and Drug Administration and Control (NAFDAC): Access to ARVs remains extremely difficult in some communities in Nigeria. Currently, access is easier only in the big towns and cities and clustered only in locations that are far difficult to reach for many people living with HIV who need the ARVs.  Implementation of PrEP may therefore face its challenges in Nigeria. Unfortunately, wide spread understanding of the potential high benefits of PreP may create a demand for the drug that cannot be met through hospital based services. The thriving black drug market in Nigeria may once again have a potential veritable market for the Truvada as a PreP. NHVMAS calls on NAFDAC to play its critcal role at this time: it need to understand the potential for fake drug sales, and position itself to play a critical important role in preventing fake ARVs sales, especially Truvada, in the market cannot be overemphasised.
2. Call to all International Partners and stakeholders working with MSMs in Nigeria:  Even in places where access to ARVs is more stable, PrEP will likely be targeted to groups most at risk for HIV, including MSMs. This would in turn require disclosure of same-sex behaviour, which could prove difficult or even dangerous in a country like Nigeria where violence, stigma and discrimination, and legal restrictions against MSM persists.  In a country where MSMs have an HIV incidence that is five times the national average, where MSMS are well know to serve as a bridge for HIV infection to the general population, addressing potential barriers to PreP access needs to be expediated now. NHVMAS calls on all stakeholders working with MSMs should address potential barriers to MSMs’ access to PreP when programmes start to roll out.
3. Call to The National Agency for the Control of HIV/AIDs (NACA) and HIV prevention implementing partners: Truvada is not a magic bullet. Trial participants also had access to suitable HIV prevention tools such as STI management, consistent and regular education on HIV prevention include correct and consistent use of condoms and lubricants, condoms,  and monthly HIV testing in addition to the pills. This may have been an important contributing factor underlying these encouraging results. Unfortunately, these additional existing HIV prevention tools ave still out of reach of the general population and less so MSMs. An estimated 90 percent of MSM globally lack access to even the most basic prevention services.  To achieve true combination prevention, we must not only significantly expand access to ARVs, but also promote much greater access to condoms, lubricant and other basic sexual health services for all those who need it irrespective of gender, sexual orientation and wealth. NHVMAS therefore calls on NACA, all HIV prevention implementing partners and programmers to intensify efforts at facilitating community access to existing HIV prevention tools even as plans are been made for the roll out of PreP.

4. Call to advocates: One challenge the trial highlighted is that adherence to drug use. Evidence show that the effectiveness of the drug increased with improved adherence. The trial reported that only about half of study participants took the medication consistently.  NHVMAS calls on all advocates and HIV community educators to include information on HIV prevention technologies in their HIV prevention messages so as to start discussion the issue of adherence, combination prevention, and the implication of partial efficacy of PreP and other biomedical HIV prevention tools being developed now prior to drug roll out.
5. Call to People Living with HIV: With more and more research evidence showing the efficacy of ARVs as potential HIV prevention tools, the demand for the global limited supply of antirovirals would increase. This will indeed call for concerted efforts between the HIV prevention and treatment field to address the potential challenges this may pose to ARV access for the two fields in the near future. NHVMAS therefore calls on all stakeholders in the field of HIV to work collaboratively as we move the field of HIV prevention into new frontiers. This is a time for joint calls on increased access for HIV treatemtn and prevention within the context of ARV use.  The field can no longer be the same again with the announcement of the results of the iPreX trial. We at NHVMAS will continue to use the result of this trial as well as those of existing and forthcoming trials results as an advocacy tool  to enhance government, partner and community engagement in HIV prevention research. As the World AIDS day
approaches, the world indeed has a calll to make: a call for universal access to HIV prevention and treatment tools and the respect for the rights and dignity of all men irrespective of their sexual orientation.

Understanding Combination Prevention: the way forward for effective HIV prevention

Understanding Combination Prevention: the way forward for effective HIV prevention

This is the reasonable way forward. Unfortunately, this is not a guiding principle applied systematically in HIV prevention,noted Dr Carlos Caceres while given his talk during the plenary session on the 21st of July, 2010.

Combination prevention required that multiple strategies are mutually coordinated and supported to ensure national impact. Currently, most programmes are dispersed, focused on behavioural communication and counselling, poorly disseminated, focused on the short term changes due to the need programe demand for immediate results. These programmes are limited and poorly evaluated and so there was limited understanding of the impact of these programmes. Worsestill, only 7% of total HIV spending was spent on HIV prevention and less than 1% is focused on MARPs.

What is combination prevention: The concept of combination prevention is an analogue to combination treatment. Currently, the concept is used in more than one way (i) combination of 2 or more intervention strategies (ii) combination of diverse strategies to meet the HIV prevention needs of different subpopulations.  (iii) strategic combination of biomedical (Male circumcision, PEP, PMTCT, ARV treatment), behaviour (BCC) and structural interventions  to address key causes of HIV risk and vulnerability in a particular population. The third definitiion is that agreed to by UNAIDS Working Group.

What are structural interventions:  These are interventions that addresses the political, physical and social domains that drives the epidemic. These will mean focusing on aspects of the environment that increases people vulnerability to HIV and decreases access; change in law and regulations; promotion of changes in cultural and social norms, creating a supportive environment; community mobilisation and empowerment; and fostering social inclusion. Good prevention planning includes understanding of human rigths far beyond protecting human rights.

Impact of combination prevention on HIV prevalence: if HIV prevention programming continues status quo, 44 million new cases of HIV will be recorded over the next 25 years. With combination prevention, there will be 29 million new cases. This means that 66% new cases are averted. In addition, structural interventions have borade development effects including addressing poverty and gender inequality. The AVAHAN project in India is an example of such structural interventions with success story amongst many others.

Take home message:  focusing on individuals for prevention is not sufficient. Combination prevention is strategic, evidence informed combining behavioural and biomedical interventions with structural strategies in a human right framwork. This will need a sustained long term response and cannot be implemented in a rigid framework.

Cure for HIV infection must now be major scientific priority, Vienna AIDS conference hears

A cure for HIV infection is scientifically feasible and increasingly necessary, but the goal requires focus and funding, said Sharon Lewin of Monash University in Melbourne, in a keynote address at the opening session of the AIDS 2010 conference.

 Antiretroviral therapy has dramatically reduced illness and increased survival, but people with HIV still do not achieve normal life expectancy relative to the general population. In addition, a growing body of evidence indicates that even very low-level virus contributes to a number of health problems. These problems – which range from cardiovascular and liver disease to neurocognitive impairment and bone loss – are increasingly linked to chronic immune activation and inflammation triggered by persistent virus. “There’s some sort of HIV-related problem that’s causing people to get sick earlier than they otherwise would have”.

The most sensitive tests can find residual HIV in almost everyone infected, including people on effective combination therapy and elite controllers who suppress the virus naturally. “There is no such thing as an undetectable viral load,” Lewin added.

The main barriers to curing HIV, are latently infected T-cells, residual viral replication, and anatomical reservoirs (such as the brain, gut and genital tract) that harbour hidden virus.

Most T-cells in the body are resting. HIV mostly infects active CD4 T-cells, which produce new virus but then soon die. In resting cells, by contrast, HIV genetic material is integrated into the host cell’s genome where it can remain dormant for a long time, but can “wake up” at any point and reignite viral replication.

Scientists do not fully understand how HIV evades the immune response and establishes latency in resting cells, but a variety of signalling molecules and transcription factors appear to play a role, and thus offer potential targets for intervention.

Intensification of antiretroviral therapy by adding more drugs has not been able to eradicate HIV in multiple studies to date. A more promising approach uses agents such as interleukin 7 (IL-7) to activate resting cells and flush HIV out of hiding. Another strategy uses compounds called histone deacetylase (HDAC) inhibitors to turn on HIV genes.

The experience of one man in Germany, dubbed the ‘Berlin patient’, offers proof-of-concept that this may be possible. Gero Hütter, who treated the patient, described the case at the IAS pre-conference meeting. The man underwent chemotherapy for leukaemia that destroyed his own immune cells and received bone marrow stem cell transplants from a donor who carried the protective CCR5-delta32 mutation, which makes cells resistance to HIV infection. Within two months after his first transplant the man showed no measurable HIV, despite stopping antiretroviral therapy. Three years later, he still shows no signs of infection.

While widespread bone marrow transplants are not realistic, Lewin acknowledged, this patient tells us that getting rid of latently infected cells and living without antiretroviral treatment is possible, and we need to learn why. Researchers are now pursuing a related approach, using gene therapy to make cells HIV-resistant.

“The international conference in Vienna will not be the conference where we announce a cure,” Lewin concluded, “but it will mark the beginning of a future where we seriously prioritise finding a cure.”

For the full report and references, visit: http://www.aidsmap.com/page/1447784