Role of Agency – Protect Patient Safety

The FDA is mandated to regulate that drugs that are approved are safe and efficacious and do not posed any risk to patient health. Biosimilars have a slight different starting point since most of the molecules have been shown to be safe and effective for decades.

Why does it take so long……..

Why does it take so long for these molecules to get through the approval process?

The biosimilar companies who have entered into the space have been traditionally innovator companies and have fallen into the same routine of creating very complex and un-necessary clinical trials to proof a known fact that these biosimilars are safe and in most cases do not have immunogenic effects. This is where it all goes wrong, these companies propose these lengthy and large patient trials to agency where FDA’s clinical team provide input and magically a large trial starts. These biosimilar companies are not specific on their intent and do not ask the basic question to FDA experts.

Is this trial necessary ?

Are there are other ways to generate totality of evidence and substantiate and remove any residual uncertainty?

Innovators make SIGNIFICANT changes to process

Most of the innovator companies have changed their processes and also have changed their manufacturing facilities without the need for large clinical trials. These changes are submitted to the agency with very sophisticated comparability analysis and in some cases some animal studies. Rarely, have these companies required a new clinical trial. Some companies have taken their product from 20L scale to 5,000L without one additional study being conducted or required by the FDA. The innovator companies have done this in existing and in new facilities where the changes in process mimics what is being done by biosimilar companies during their development.

Are clinical trials necessary ?

This notion of large clinical trials is not a requirement. The regulations or FDA has not made it so. The requirement is for the product to be similar and with no clinically meaningful differences, and no residual uncertainty. The biosimilars companies have chosen to remove residual uncertainty by embarking on these very expensive trials which are often conducted as global programs mired with issues of clinical conduct, data traceability and most important different standard of care. In some instances the clinical generates data that is confounding and is some cases not trustworthy. The data generated in these trials bring into question the process used to produce the molecule. The biosimilar companies put themselves in a position where FDA question the control of material, the data collected at the  clinical sites which often located outside US, Europe or other countries with similar standard of care.

The regulations do not call for these complex trials. The agency is faced with the data that are being presented by the biosimilar companies which puts in question similarity of the molecule. Equally important, based on the data presented the FDA looses confidence Quality system being used to control the conduct  of clinical trial and integrity of the data . As mentioned earlier the innovator companies have been making these changes for decades without a need for these expensive backflips and rely on well planned comparability studies which justifies the change and proofs before/after similarity

The agency is correct in establishing very rigorous statistical analytical requirements and ensuring that these molecules do not pose any immunogenic concerns to the patient. Atmthe same time the regulations do not call for these very expensive and lengthy trials. We can agree, that in some cases there is a need to generate patient data, but the size of the trials and the unnecessary patient exposure should be questioned.

Process and Analytical Characterization Core

Based on my meetings with agency, I see the agency consistently trying to guide biosimilar companies to propose innovative ways to establish the “Totality of evidence” and providing input on simplifying their approach. The base of the pyramid in biosimilar development is the analytical and process characterization. The rush to get products into the next phase often shortcuts this process and leads to problems in the similarity exercise and in some cases in the manufacturing. The case in point was illustrated in the initial application made by Sandoz where company manufactured product with concentration that failed the equivalence testing, leading them to manufacture more product and the corresponding delays.

Affordability of Biosimilars Impacted by Costly Trials

Sansumg, Sandoz, Amgen and other companies who have embarked on these expensive trials cannot financially justify a significant reduction in price of their biosimilars. The expected reduction in price has been forecasted to be in the range of 15-30% of originators price, primarily driven by these un-necessary trials. If you look at clinicaltrials.gov hundreds of patients have been un-necessarily exposed to these trials that do not meet the intention of efficacy and safety. The design of the trials follows a similar path as the originator used to obtain initial approval.

There is ample scientific understanding and safety of the proposed biosimilars. It’s the responsibility of the biosimilar developer to show product comparability in the same way that has been done for decades by the innovators. The money and time should be spent on ensuring that the analytical characterization is solid, process development process is methodical and that the manufacturing process has total control of the critical process parameters.

FDA Friend or FOE ?

In my opinion the FDA is not our FOE, the internal company regulators are the FOE. The are mostly responsible for the lengthy delays in product approval by proposing long, complex and expensive clinical trials. The agency requires complete understanding of the molecule, its mechanism of action, its statistical comparability. It calls for the reproducibility of the manufacturing process and most important the strength of the quality system as an internal self-auditing arm that understands and ensures patient safety.

FDA Best Consultants

The agency has a system and experts to challenge every facet of the development, manufacturing, clinical and most likely have seen the challenges being faced. The test for biosimilar developers is to use the pathway and all the agencies expertise and ask the relevant questions that allow the agency to share their collective wisdom. The FDA through its review process has content, knowledge and most important has compiled combined experience that can aid the speed of approval and reducing need for large clinical trials.

In my opinion the questions to the agency should revolve around how the biosimilar developer can provide totality of evidence and remove any residual uncertainty while reducing un-necessary patient exposure. The key to obtaining the desire response from the agency revolves around the demonstration of the applicants understanding of the molecule, similarity the innovator and in the areas of dissimilarity understanding their clinically meaningfulness.  The biosimilar company should have deep scientific understanding of the mechanism of action how their in-vivo and in-situ side by side characterization evidences their position.

Would love to hear your opinion on this topic….

As always I welcome your comments and you can contact me at [email protected] or [email protected]