March 15, 2012 8:39 pm
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Proposed changes to diagnostic criteria of the new diagnostic and statistical manual of mental disorders (DSM-5) are likely to encourage a symptom-specific approach to autism drug development, according to autism experts interviewed by BioPharm Insight. Yet, the FDA may be reluctant to follow suit, according to an agency executive.
The fifth edition of the DSM--the “Holy Grail” of diagnosing psychiatric disorders--proposes the umbrella term of autism spectrum disorder (ASD), replacing the current “autistic disorder.” ASD will incorporate current diagnoses of Asperger syndrome, pervasive development disorder not otherwise specified (PDD-NOS), Rett syndrome and childhood disintegrative disorder, thereby eliminating these diagnostic distinctions.
DSM-5 is expected to be officially published in May 2013, according to Dr Darrel Regier, director, division of research, American Psychiatric Association (APA) and vice-chair of DSM-5 Task Force. New ASD diagnostic criteria will emphasize social communication deficits as well as fixated interest and repetitive movement, while the severity of symptoms will be characterized as mild, moderate, severe and extreme, Reiger said, noting individuals such as Asberger and PDD-NOS patients would still fall within the spectrum.
Changes to autism diagnostic criteria will encourage drug developers to focus on specific symptom clusters, for example, specific language or social deficits, said Dr Glen Elliott, chief psychiatrist and medical officer at Children’s Health Council, Palo Alto, California.
Janssen Pharmaceuticals/Johnson and Johnson’s (NYSE:JNJ) Risperdal (risperidone) is currently the only FDA-approved medication for behavior-related problems associated with autism. It is indicated for treatment of irritability associated with autistic disorder in children and adolescents aged 5-16 years.
Autism experts have often expressed dissatisfaction with a drug that targets only one aspect of the disease, said Dr Richard Frye, director of autism research, The University of Arkansas for Medical Sciences. Yet, with DSM-5 one can no longer criticize drugs that target only one aspect of autism, he said.
For example, Elliott and Frye noted BioMarin’s (NASDAQ:BMRN) Phase II drug Kuvan (sapropterin) may have positive effects on certain aspects of language in autistics. Kuvan was found to help a child use language for more social purposes such as interactions, this news service previously reported.
Targeting repetitive behavior in autism is still a significant unmet need that drug developers should view as an opportunity noted, Robert Ring, VP Translational Research at Autism Speaks and previous head of autism research at Pfizer (NYSE:PFE).
Dr Anatoly Belilovsky, medical director of Belilovsky Pediatrics, said doctors will not consider a drug based on its adherence to DSM-5 diagnostic criteria; they would choose it based on its ability to treat a patient with a particular constellation of symptoms, he said.
However, autism drug developers would have to demonstrate compelling rationale to investigate the drug for a specific symptom when targeting a particular aspect of a defined psychiatric syndrome, as the FDA generally approves drugs for psychiatric syndromes in their entirety (e.g. schizophrenia or MDD), said FDA’s head of the Division of Psychiatric Products, Thomas Laughren. Yet he said if a company could make a good case for investigating a drug for a particular aspect of a defined psychiatric syndromewithin a psychiatric disorder, then it would be considered.
An example of this is schizophrenia, where the FDA has approved standardized approaches for targeting cognitive dysfunction in these patients, Laughren said.
The FDA used to approve drugs for broad indications, though the supporting studies were focused on a particular syndrome, Laughren said. The FDA has moved away from this approach because some companies had attempted to make claims that could be promoted for any specific syndrome that fell under a broad umbrella, he explained. For example, a company that had an approval for the “management of the manifestations of psychotic disorders” based on studies in schizophrenic patients might have tried to promote that drug for “psychosis of Alzheimer’s disease,” though it did not actually conduct studies in this population, Laughren noted.
Seaside Therapeutics is currently assessing STX209 (arbaclofen) for the treatment of social withdrawal in subjects with ASD. Curemark’s Phase III trial of CM-AT targeting “core symptoms” of autism has completed, though additional details have not been disclosed.
Curemark declined to comment for this article; Seaside did not return requests for comment.
Impact on clinical trial design
Enrollment criteria for autism trials are unlikely to change as trials use the Autism Diagnostic Observation Schedule (ADOS) or the Autism Diagnosis Interview–Revised (ADI-R), not the DSM-IV, to enroll patients, according to Frye. However, it is unclear how the ADOS or ADI-R correspond with the DSM-5, Frye said. According to Regier, these measures will correlate well with the DSM-5 ASD diagnostic criteria and enrollment criteria are unlikely to change.
The DSM-5 modifications will be great for drug development, as there will be greater standardization in clinical trials, said Dr Craig Erickson, chief, Christian Sarkine Autism Treatment Center, Indiana University School of Medicine. With hardened criteria, there will be better, clearer studies that are easier to interpret, he said. DSM-5 changes will be a positive for research as the improved diagnostic clarity would ensure proper enrollment criteria, Ring agreed.
Erickson noted that there is often a bias in clinical trials, where high-functioning patients are typically enrolled as they are more readily able to tolerate routine procedures such as blood tests part of clinical trials. Further, it is easier to make improvements in less-impaired children, Elliott said, noting the Phase II Kuvan in autism trial included children with IQs in the 50-60 range as well as Asberger patients.
To avoid a bias in developing treatments only for higher-functioning patients, it would be especially advantageous to target specific symptoms rather than a broad lump of ASD so that specific interventions can target symptoms for a particular severity, for example stereotypic motor movements, Elliott said.
A controversial analysis by Dr Fred Volkmar, chief of Child Psychiatry at Yale-New Haven Children’s Hospital, recently publicized by mass-media outlets indicated that many high-functioning autistic patients would essentially lose their diagnosis under the DSM-5 criteria. When cross-linking DSM-IV, the current edition, and DSM-5 criteria, there was “not a perfect match,” he told this news service. Accordingly, as some confusion may arise over which individuals would fall within new diagnostic criteria, it would be more productive to target specific symptoms, rather than autism as a whole, several experts noted.
Volkmar noted 60% of high-functioning autistic patients with social interaction problems, but normal IQ, would lose their diagnosis. According to Volkmar, of people with IQ above 70, only about 44% would qualify for the new ASD label and 76% of Asberger patients and 84% of PDD-NOS patients would lose their diagnosis.
However, Regier deemed Volkmar’s analysis as “flawed.” It is impossible to make those judgments based on his analysis as it was a retrospective study with a “skewed” sample not representative of a clinical population, Regier said, adding Volkmar’s assessment was hypothesis generating, rather than testing.
Volkmar’s analysis focused on 372 high-functioning autistics out of a sample of 1,000 patients diagnosed in 1993 as part of the DSM-IV field trials. Regier noted these patients were identified with DSM-III-R criteria, therefore it is “not credible” to make Volkmar’s conclusions based on a “stretch” from DSM-III-R to DSM-5.
The APA is in active discussions with the Journal of the American Academy of Child and Adolescent Psychiatry to publish a commentary alongside Volkmar’s analysis, refuting his assertions, Regier said. Volkmar’s analysis as well as the APA commentary is expected to be published on the online edition of the journal within a few weeks, Regier said.
Volkmar served on the DSM-IV task-force, but resigned early on from DSM-5’s task force. He refuted Regier’s assertions, claiming there are now two studies showing the same results as his analysis. He added he is aware of three more studies with similar findings going through peer review process
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