Perspective: A Modern Progressive Approval System for Rare Diseases

The recent dramatic increase in the number of orphan drug designations has prompted patient groups, pharmaceutical companies, legislators and many other stakeholders to look for ways to accelerate the delivery of innovative new medicines to people with rare diseases. In particular, patients suffering from illnesses for which there are no adequate licensed therapies want access to promising new products earlier in the drug development cycle.

Against this backdrop, there is a growing urgency to rethink the regulatory review process itself. One option certainly worth exploring is a more progressive assessment and approval mechanism under which potential therapies for rare diseases are reviewed.

Certain dynamics make rare diseases ideal subjects for such regulatory innovation. These include the relatively small patient populations, the concentration of clinical research activities at medical centers of excellence and the high level of specialization of the treating physicians. Another unique feature of rare diseases is the wealth of scientific knowledge among patients and their families and, as a result, the extent to which they can interact with specialist doctors about diseases and their evolution.

Taken together, these factors make the rationale for 'experimenting' with less conservative regulatory mechanisms very compelling.

Continuum of Drug Development

The idea of progressive approval has been around for some time; indeed there are already positive examples of this concept. Perhaps the most significant is the "conditional approval," which has been practiced in Europe since the early 2000s and serves as a good template for what could be done elsewhere.

A conditional approval is based on the premise that the body of data submitted to regulatory authorities for an investigational product is encouraging, but the results are often short-term in relation to the natural course of disease progression. As a result, more data and longer patient follow-up are required. Approval is not "final." Rather, the regulators and the sponsors must carefully define the remaining obligations or the "conditions" of the conditional approval. Failure to meet these conditions, or the appearance of results that do not support earlier strong data, normally leads to cancellation (non-renewal) of the conditional approval.

Orphan drug development might, therefore, be viewed as a continuum, with close interactions between clinical trial sponsors and regulators. Drugmakers receive regular consultations and scientific advice from the authorities at critical points in development. The length of clinical studies and the possible use of surrogate markers of innovative trial endpoints are some of the key points that need to be discussed. It should also be possible to envision cases where chemistry, manufacturing and controls (CMC) or quality assurance (QA) data still need to be completed, provided there is a clear plan to resolve those issues.

In Europe, conditional approval is possible for three categories of investigational medicines: orphan drugs, medicines used in emergency situations and those treating seriously debilitating or life-threatening diseases. Yet statistics suggest that developers of orphan drugs are not using the conditional approval pathway nearly as much as they could. To date, 40% of orphan drugs have been registered through the "exceptional circumstances" regulatory pathway, while just 5% were registered for conditional approval.¹ In other words, in more than half of cases, sponsor companies chose to register products under the normal marketing authorization pathway.

Instead, conditional approval should become the default pathway in rare diseases-provided sufficient dialogue has taken place between patients, physicians, drug developers and the regulators, and excluding cases where the rules for authorization under exceptional circumstances apply.

Both sponsor and regulator should indicate what is known on every key aspect of the new drug, as well as what remains to be demonstrated and confirmed. This includes information on the drug's clinical benefit, its efficacy and safety profile versus what is known of the natural disease history. It also includes CMC and QA issues. All stakeholders should be asked to consider the product's overall benefit:risk assessment and determine how risks can be managed.

It is important to consider the feasibility of meeting the obligations agreed under the conditional approval; product availability may have a dramatic influence on the willingness of patients to participate in well-controlled trials in centers far from where they live.

Early Dialogue and Flexibility

The timeframe in which the remaining obligations must be completed is often a concern for regulators. There are certainly cases when sponsor companies face technical, operational or financial challenges. Therefore, the company and the regulator should discuss up front the feasibility of meeting the conditions. A smaller company-typically one with fewer resources-should, in particular, be given time by regulators to consider an alliance with another party to fulfill its obligations during the agreed timeframe.

Finding operational solutions to build a complete understanding of investigational drugs is the responsibility of sponsor companies. Patient benefits are, however, key principles behind any early-access program. It is, therefore, entirely appropriate for patient groups to participate in dialogue with regulators, explicitly evaluating the benefits and risks of accelerated development. Ideally, there should be agreement among patient groups, their physicians, regulators and the new drug's developer.

Once an orphan drug is granted a conditional approval, the collection of patient-reported outcomes becomes easier by simple virtue of the fact that more patients are using the product. This creates an additional important source of information that can help characterize the new product before it receives final approval.

It is difficult to estimate in advance what percentage of orphan drug designations will eventually bring the substantial efficacy and safety data needed for final approvals. However, an innovative, conditional regulatory approach may well double the number of approvals (albeit on a conditional basis) in three to five years. Consider that there are still only about 300 approved orphan drugs, while there are some 6,000 rare diseases worldwide, and it has taken almost 30 years since the US Orphan Drug Act was passed to reach this stage. Doubling this figure within five years is an ambitious goal, but one that patients are waiting for and deserve.

References

1.     Llinares J. "A regulatory overview about rare diseases."' Advances in Experimental Medicine and Biology, Springer, Heidelberg, Germany. 2010, Volume 686, pp. 193-207.