By Ed Miseta, Chief Editor, Clinical Leader
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Drug development generally takes a pretty standard path from discovery to commercialization. Preclinical testing leads to safety and efficacy testing in Phase 1 and Phase 2 trials. Those studies lead to a larger Phase 3 that generates data necessary to secure a regulatory approval. But there is an additional path sponsors can take that is known as head-to-head trials (H2H). These studies test your medicine against others that are already on the market, and can determine if your treatment is a better option for patients.
“With any clinical trial you are hoping to gain a risk/benefit understanding of your particular drug or medicine,” says Lotus Mallbris, M.D., Ph.D., vice president and global head of immunology product development for Eli Lilly and Company. “But you can’t test everything. For example, with a condition such as psoriasis or atopic dermatitis, itch relief is important to doctors and patients. Unfortunately, that is generally not a primary endpoint. The primary endpoint would normally be clearing of the skin. Still, the product’s effectiveness at reducing itching, as compared to other products, is something you might want to know to help patients understand if a product helps with other important dimensions of their disease that may not be as relevant to regulatory bodies.”
An H2H trial could identify benefits not noted during the clinical trial that would be of interest to patients, physicians, and payers. The benefits can then be used to change the standard of care. The additional evidence gathered can be valuable to doctors attempting to determine the right medication for their patients.
One path for an H2H trial is to take your treatment through the normal trial process and then conduct the H2H trial after gaining regulatory approval. The other option is a parallel path, where the H2H study is performed alongside the Phase 3 study. Regardless of the path, the overall goal is to show a better safety or efficacy profile than current treatments.
“There is definitely a patient-centric angle to these trials,” states Mallbris. “With a typical Phase 3 trial, you are somewhat limited in how much patient input can be incorporated. That is especially true when the input provided does not tie directly to the identified endpoints. With an H2H trial, we are heavily involving patients. When comparing our medicine to an existing treatment, we might explore whether our drug helps improve quality of life. That helps us treat patients with the medicine that addresses their needs.”
In Lilly’s immunology portfolio, eight different H2H clinical trials have been conducted thus far. Four of those trials were conducted in parallel with a Phase 3 trial and four were conducted after it. Although the benefits are attractive to a sponsor company, H2H trials can present some unique risks.
BE PREPARED TO BACK UP YOUR CLAIMS
Once a company has regulatory approval, it can commercialize the drug and create a marketing campaign to address patients and physicians. If a company opts to then conduct an H2H trial, and the results are not as anticipated, it could jeopardize those marketing efforts.
“You certainly must be confident in your treatment outperforming the standard of care,” cautions Mallbris. “Each time we conducted an H2H trial we felt our treatment would bring more value to patients. But once you make that claim, you have to back it up with evidence.”
According to Mallbris, all potential sources of bias must be removed to give both treatments a fair chance of coming out ahead. “You want a level playing field that does not favor either of the participants,” says Mallbris. “These are blinded studies, and our goal is fair, unbiased science. If we discover that our treatment is better, we want to have that science to back up our claims. We do not want our methods to come into question.”
A TEMPLATE FOR FUTURE TRIALS
While the main goal of an H2H trial is determining which treatment is better for patients, what Lilly learns from these trials also helps the company improve future trials. For example, discoveries made during these trials could determine future endpoints, help researchers understand how to make trials more patient-centric, or provide insights into the science that were not previously known.
“If I had one bit of information to share with a new head of clinical development on how to conduct their H2H trial, it would be to know your science, your molecule, and your competitor very well,” advises Mallbris. “Let’s be honest, in any H2H trial no one wants to lose. Your drug may not be able to elevate every outcome, but you must be able to elevate those outcomes that are important to the patient. The interests of the patient must be paramount.”
If two drugs are equally safe and effective, but one can be taken orally and the other has to be injected, doctors and patients will opt for the one that is easier to administer. In that case there is no reason for physicians to recommend your product. If your H2H trial cannot demonstrate that it’s better, you have lost the battle.
THREE OPTIONS TO SECURE DRUG PRODUCTS
While there are benefits to be gained from a successful H2H trial, those studies can also create unique challenges. One of those is cost. Mallbris notes that, as compared to a placebo-controlled trial, an H2H study can carry 10 times the cost, and that’s provided you are able to acquire the competing drug needed for the study.
“There is no requirement for a competitor to provide you with their medication for the trial,” she states. “Even if you are able to purchase the medication, there can be a significant cost associated with the treatment. That is likely the first challenge you’ll face.”
There are generally three routes you can take to gain access to the competing product. Since it is an approved medication, sponsors can purchase it directly from the manufacturer or a qualified wholesaler. That can be costly, depending on the price of the treatment. The product can also be obtained directly from the pharma company via a like-kind exchange, where one of your products is provided in trade for the product desired. The third option is receiving the treatment through the TransCelerate consortium, which helps facilitate the exchange of medicines between member companies.
BLIND YOUR PRODUCTS TO PREVENT BIAS
The next challenge relates to getting the two treatments into the hands of physicians and patients. H2H trials, and both treatments, must be blinded to both the physicians administering the treatments and the patients taking them. That creates an additional challenge of blinding the treatments prior to them reaching the clinic.
"If I had one bit of information to share with a new head of clinical development on how to conduct their H2H trial, it would be to know your science, your molecule, and your competitor very well,”
“Blinding H2H trials is very difficult because of challenges particular to these trials,” says Mallbris. “The packaging of the drugs can be different when they arrive at the clinic because they are coming from two manufacturers. Sometimes they may involve an injector that looks different. Even the treatments themselves can look different in terms of shape or color. If a patient has taken either product in the past, there is a chance they will recognize it. If that happens, you have bias, and the trial is no longer blinded.”
The job of making the treatments look the same is performed within Lilly and is another significant hurdle. Mallbris notes the task can seem almost impossible given the timelines established for the study. She notes the process of making the two drugs look alike can take up to nine months.
The speed of an H2H trial can also present challenges. Recruitment for an H2H trial can be completed quickly, since patients and physicians are given access to two FDA-approved drugs that are known to be safe and effective. For that reason, thousands of patients can be recruited fairly quickly.
“The enrollment goes very fast,” states Mallbris. “A trial that might normally take a year can be over in a matter of months. While a faster trial seems like a benefit, all the tasks that must be completed, such as data gathering and data management, are suddenly fast-tracked.”
Lilly does outsource studies to CROs, and the speed of H2H trials makes the role of the CRO critical. If the trial is being conducted in parallel with a Phase 3 trial, the pressure on your outsourcing partner is even greater. In those instances, it pays to select a CRO that has experience performing these trials.
Because of the cost associated with H2H trials, Mallbris recommends undertaking them only when the benefits of taking that path are clear. “Standards of care are always evolving, and physicians and payers like to see an H2H comparison to know which product is better. They want to see the proof. At the same time, every dollar that we spend on an H2H trial is a dollar that can’t be spent developing an innovative treatment for our patients. This is why you must understand your science and your product. The decision to conduct an H2H trial is not one we take lightly. You must know that action is appropriate and be able to defend it.”