Vantage point – Patient-reported data gain traction in FDA decisions

No matter how the US FDA deals with Sarepta Therapeutics' Duchenne muscular dystrophy project eteplirsen, one potential solace is that because of fierce activism surrounding the project regulators might now be more attuned than ever to incorporating patient advocates' views into agency action.

Patient-centred research has been a growing factor in the FDA’s decision-making process, spurred in recent years by requirements under the 2012 reauthorisation of the Prescription Drug User Fee Act. Now legislation pending on Capitol Hill aims to strengthen this outlook, with “patient experience data” to be incorporated into the clinical packages submitted with candidates seeking FDA approval.

At issue is how to collect and standardise data that can be perceived as subjective, as well as whether to include efficacy endpoints or restrict the analysis just to safety and tolerability. But at its core this is an effort to understand that clinicians and patients sometimes have different views on what constitutes a treatment advance.

“The important thing is not to presume what patients care about,” says Sara Radcliffe, chief executive of the California Life Sciences Association.

Patient involvement is not necessarily new – certainly, the activities of HIV activists in the 1980s and 1990s did much to speed development of new antivirals and establish the accelerated approval pathway. What is changing is that the involvement of patient viewpoints is becoming more systematic through a series of FDA meetings to improve understanding of their needs.

Talk to the patients

Eteplirsen has been a flashpoint in the relationship between regulators and the patient advocacy community, as the recent advisory committee meeting drew dozens of speakers, including unprecedented testimony by a sitting member of Congress who urged the FDA to speed its review of the project.

Emotions ran high enough that the meeting drew a rare appearance from the agency’s drug review chief, Janet Woodcock, who advised expert panellists that taking patient views into account is acceptable under FDA regulations, and met patients and their families afterwards.

That adcom meeting, in which panellists voted against approval, was in some ways the first formalised public hearing that agency officials have held to hear the views of patients with Duchenne muscular dystrophy. The key message from the patient advocates was that they cared less about the thin Sarepta database and more about having a chance to try the agent.

Since the Food and Drug Administration Safety and Innovation Act in 2012 the agency has been required to consult patients on drug development matters – so far, 18 meetings have occurred in conditions ranging from alpha-1 antitrypsin deficiency to lung and breast cancers, but muscular dystrophy has not been on the agenda.

While it is hard to say how or even if those meetings have yielded a better use of patient-based data in regulatory decisions, some advocates praise it for being a step towards better understanding of how patients view their treatment.

“This is still in FDA culture a very significant shift,” says Eric Hargis, executive consultant with the Colon Cancer Alliance. “Historically, [FDA decision-making] was strictly data-driven, as if, quite frankly, this didn’t involve somebody’s life. It was that cut and dried, an evidence-based numbers game. We really appreciate that in the FDA leadership there is a movement to recognise that we’re not treating a disease; we’re treating people with a disease.”

Legislation called 21st Century Cures that has passed the US House of Representatives and companion bills in the House requires the FDA to establish a framework for drug developers to include patient experience data in their regulatory submissions. The legislation has not passed the Senate, although advocates are working on the possibility of slicing the bill into several parts to give it a better chance of passing the upper house.

First, do no harm

Much of the work being done so far is on the safety and tolerability side of the equation. At its heart is a disconnect between how clinical trial evaluators and enrolees sometimes measure adverse events.

For example, a high rate of dose interruptions or reductions in the use of tyrosine kinase inhibitors (TKIs) in cancer suggests that, while clinicians consider side-effects manageable, patients often find otherwise. So Paul Kluetz, associate director of the FDA’s office of haematology and oncology, told specialists during a session on this topic at the Asco scientific meeting.

The difference between previous treatments with chemotherapy and the TKIs is that the former involved short infusions and durations of treatment with a homogenous side-effect profile, and the latter are taken daily for a long period and have a wide range of side effects.

“Previously low-grade, kind of bothersome toxicities are now toxicities that people are living with for a long time,” Dr Kluetz said.

This was an essential factor in the National Cancer Institute’s tool called PRO-CTCAE, a patient reported version of a standardised lexicon for reporting adverse events in trials called CTCAE, which is completed by clinicians.

As for fears about the subjective nature of patient-reported data, Ethan Basch, a University of North Carolina oncologist who spoke to the same Asco audience, said the same thing was true when clinicians assessed adverse events.

“In other studies we looked at the inter-rater reliability of clinician CTCAE reporting for systematic toxicities, and the inter-rater reliability is actually quite low,” Dr Basch said. “We have to understand that there are potential problems with the existing model of clinician reporting of this information.”

That patient-reported data can be accurate is a position also taken by Dietmar Berger, Roche’s head of oncology and haematology clinical development.

“There’s actually good data from various studies that indicates that the patient assessment of some of the adverse events is actually very accurate,” Mr Berger told EP Vantage at a media event during Asco. “We want to hear how the patient really is doing. That is what the new patient reported tools allow us.”

The efficacy equation

More difficult is whether and how efficacy can be shown using patient-reported outcomes. Mr Berger points to the example of Jakafi, which won approval partly on the basis of a myelofibrosis symptom score endpoint in one of its pivotal trials, but this is an uncommon event.

This is an issue of which the FDA appears to be aware. Dr Kluetz notes that one problem in oncology is that many trials are conducted only in asymptomatic subjects in generally good health aside from their cancer, so showing an improvement in symptoms and function is hard to do.

“An alternative, and what we may see in the future, is enriching [clinical programmes] with symptomatic patients in additional trials to really target symptom benefit,” he said.

Outside oncology, California Life Science’s Association’s Ms Radcliffe notes that in chronic disease prevention of degeneration or improvement in physical function, or even more convenient dosing, could be more important to patients than biologically driven endpoints that clinical trials often try to achieve.

“Understanding what patients consider to be an advance is critical,” she says.

Thus the FDA’s ongoing meetings with patients might be laying the groundwork for regulators and drug developers alike to design trials that include endpoints centred on patient preferences.

There might never be a day when the FDA backs off from demanding strictly objective endpoints in the clinical trials used to support approval. However, the move is on to incorporate the patient perspective on how new agents affect their daily lives, and this will no doubt shift the risk-benefit equation in many future approval decisions.

To contact the writer of this story email Jonathan Gardner in London at or follow @ByJonGardner on Twitter

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