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Adaptive Clinical Trials in Orphan Drug Development

Authored by James Sheppard

The global pharmaceutical market is currently facing one of the toughest challenges to date. With blockbuster drugs coming off patent and diminishing pipelines big pharma are looking towards alternatives to provide renewed revenue. One avenue being explored by companies such as GSK and Novartis is Rare Diseases. Rare Diseases research is traditionally conducted in small biotechnology companies or academic institutions, however it can be increasingly found at the homes of big pharma.

Rare disease research and drug development has been historically very difficult however new regulation and investment has seen the field expand considerably of late. One challenge that remains is conducting clinical trials. Patient populations are by their very nature extremely small often numbering less than 1000 patients globally. This means conducting clinical trials to produce sufficient data to satisfy regulatory bodies is often extremely difficult. Therefore many companies shy away from the most neglected ultra-rare diseases for fear of not gaining regulatory approval and wasting vast amounts of money. The rare disease industry has seen some significant changes recently with regulatory barriers lowered and significant investment from big pharma and venture capitalists, however in order to progress further a paradigm shift is going to be required in the way rare disease clinical trials are conducted. One possibility is the use of adaptive clinical trials.

An adaptive clinical trial is one where the data is collected during the trial is monitored and analysed as the trial is running in order to make adjustments to the trial as it continues. Adaptive trials have also shown promise in smaller proof-of-concept studies such as Pulmatrix’s  PUR118 trial which used an adaptive design to assess a new COPD drug. The European Medicine Agency (EMA) stated in a recent draft paper that ‘adaptive designs would be best utilized to cope with difficult experimental situations.’ Below is a graphically representation of how an adaptive trial differs from traditional clinical trials.

Adaptive Clinical Trials

Image Courtesy of TOPRA 

The traditional drug development process is long and expensive which includes phase I,II and III trials and post approval phase IV trials. For rare diseases this process is simply too long and expensive and has been deemed unacceptable by many patient advocacy groups. The Duchenne Muscular Dystrophy patient group Parent Project MD stated in a policy paper ‘In DMD and other rare diseases, adaptive designs which allow modification of traditional randomized controlled trial structures are needed to better measure the safety and effectiveness of experimental agents within reasonable time periods for registration purposes’. Therefore, by using adaptive design methods the whole drug development process can be shortened without compromising the efficacy of drug and validity of the data. Therefore this can accelerate the drug development process saving companies time and money.

Biotechnology companies, the traditional home of rare disease research, struggle to take a drug through complete clinical development due to the extreme cost, typically over $1bn, and time, around 10-12 years, adaptive approaches may offer an alternative. Adaptive trials have the ability to reduce costs, reduce time (typically by around 6 months), reduce the need for large scale phase II/III trials and increase the information per dollar ratio, all with significant benefit to researcher and companies alike. The information per dollar ratio is particularly prevalent issue as with less patients you need to collect more data to satisfy regulators. The field of rare disease research is often at the forefront of new developments and the very nature of rare diseases lends itself perfect to adaptive trial designs.

We are beginning to witness more and more adaptive clinical trials within rare diseases and a recent example is NewLink Genetics Phase IIB/III trials of Tergenpumatucel-L Immunotherapy in Patients with Non-Small Cell Lung Cancer. The phase IIB study is running three separate arms in order to establish the dose level followed by the phase III study where a planned interim analysis and sample size re-estimation is planned. “This study is designed to test the hypothesis that patients treated with HyperAcute immunotherapies may be sensitized to subsequent treatments with chemotherapy while also evaluating whether survival benefits observed in our Phase 2 study can be reproduced in a larger controlled Phase 3 study,” said Dr. Nick Vahanian, President, Chief Medical Officer, NewLink Genetics.

It is important to note that adaptive trials are not the answer to all clinical problems many trials cannot be adaptive due to sample size problems and statistical issues. However when starting down the adaptive design path many extra costs can be occurred such as educating clinicians and statisticians, installing the correct infrastructure to allow data to be recorded and technical challenges such as drug supply. However companies such as Aptiv Solutions and other CRO’s are now beginning to see the benefit and offer a cheaper and easier alternative to conducting the trial yourself.

The benefit to companies and patients in the rare disease space is clear. By reducing time and costs patients will be able to access drugs faster and easier and overcome some of the market access challenges for orphan drugs. Rare disease drugs are expensive to develop and sell typically costing over $250,000 a year therefore any saving in the development process will be passed on to patients and payers alike. Adaptive trials offer the possibility to help reduce not only the financial burden but the time constraints too.

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