Fig. 12.1
FDA foundation building for clinical trial drug development
As the scientific (e.g., pathophysiology, mechanism of action [MOA], effect of intervention) and clinical data (post IND phase, such as early and later phase clinical testing) are collected and analyzed, it is sent to regulatory agencies for review and feedback on the progress of the clinical development program. After preclinical testing in the laboratory and in animals, regulatory agencies (the FDA in the U.S.) must give approval before human trials may commence.
In Phase I trials, healthy human volunteers are typically given various doses of the compound in order to study its pharmacokinetics (PK), pharmacodynamics (PD), and, to some extent, its safety. Phase II trials are generally designed to elucidate a safe and effective dosage range in a limited number of patients with the condition the drug was developed to treat. Finally, Phase III clinical trials are conducted on large numbers of patients with the condition for which the drug was developed in order to assess the drug’s safety and efficacy.
Once all of the required information from the multiple trials is collected and analyzed, it is submitted for regulatory approval in the form of written reports. A team of experts from multiple disciplines reviews portions of the data package and determines whether the drug is both safe and effective for the indication for which it was developed. Of interest is the fact that the FDA simply approves the proposed labeling (package insert) for the drug, and not the drug itself, yet it is illegal to market a drug for treatment of any disease without FDA-approved labeling. After the labeling is approved, the product continues to be monitored in an ever-enlarging population of patients as long as it remains on the market. After a drug is in general use, its sponsor may compare it with others used for the same indication either to bolster superiority claims or to study further the safety and efficacy of the product as part of a regulatory commitment at the time of original FDA approval. Such activities are known as Phase IV post-marketing studies.
Although this is the general paradigm for the approval of many drugs, certain exceptions can be made, because of issues such as the ethical conundrum of giving a placebo in lieu of a potential disease modifying treatment to a patient afflicted with MD. In these cases, some groups, such as PMDD, advocate for a comparison between the active drug and the expected natural history course of the disease. Although this is entirely understandable, given the variation with MD—even within families—this may prove difficult unless additional natural history studies are conducted.
Approved Products and Treatments
There is only one product tentatively approved for the treatment of MD anywhere in the world. As mentioned earlier, PTC Therapeutics’ ataluren was granted marketing authorization (tentative approval) in the EU under the trade name Translarna™ for the treatment of DMD in ambulatory patients aged five years and older. Translarna™ is approved to treat the underlying cause of DMD. The European Medicines Agency has designated ataluren as an orphan medicinal product and the FDA has granted orphan drug designation to ataluren for the treatment of DMD.
The ongoing Phase III Ataluren Confirmatory Trial is a randomized, double-blind, placebo-controlled trial designed to confirm the safety and efficacy results seen in an earlier Phase IIb study. The confirmatory study was designed to enroll 220 participants at approximately 58 sites in North America, South America, Europe, Israel, Asia, and Australia. Successful results of this trial would provide the basis for a full approval decision in the EU and the U.S., as well as in other countries.
According to DuchenneConnect: [1]
Based on estimates regarding patient enrollment, initial, top-line data from the Phase III clinical trial were expected in mid-2015. If trial results support approval and FDA approves their application, Translarna™ could be available in the U.S. as early as the second half of 2016. PTC plans to apply for approval in other countries following U.S. approval.
Potential Treatments for MD
A total of 247 MD studies were identified (on October 30, 2014) using the search term “muscular dystrophy” on the Website titled clinicaltrials.gov—a government mandated Website dedicated to posting all clinical trials being conducted in the U.S. It is important to note that other studies may be ongoing—and not recognized on this Website—as they may be conducted in Europe or other non-U.S. regions. Clinical trials conducted in EU and European Economic Area (EEA) can be found at www.clinicaltrialsregister.eu.
It should be emphasized that U.S., Europe, and Japan are the only countries currently following International Conference of Harmonization (ICH) guidelines on good clinical practice and the conduct of clinical trials. This is important to note because a clinical dossier for registration purposes can be filed simultaneously in all ICH countries, though, in the author’s opinion, there are still subtle differences between these geographies meaning that this is not always achievable.
It is also important to note, for those considering participating in a clinical trial outside of ICH countries, that the other countries may not have as rigorous clinical trial requirements and this should be factored into any clinical risk/benefit analysis.
Of these 247 studies, 105 studies were found for “Duchenne muscular dystrophy” and 124 studies were found for “Becker muscular dystrophy,” though it should be noted that most of these studies overlap (because they have a similar pathology), thus are double-counted and not unique. Most DMD and BMD studies focus on treatment of the heart and lungs, where complications can cause early mortality in DMD patients.
Only seven studies were found using the search term “FSH or FSHD”; however, 21 studies were discovered for FSHD using the full search term, “facioscapulohumeral muscular dystrophy,” which reinforces that how one conducts a query may influence the number of studies discovered.
The rest of the studies—about half—are associated with other types of MD as depicted in Table 12.1.
Table 12.1
U.S. clinical trialsa for the treatment of the nine major types of MDb
Type of MD/search term | Number of clinical trials |
|---|---|
Duchenne muscular dystrophy | 105 |
Becker muscular dystrophy | 124 |
Facioscapulohumeral muscular dystrophy | 21 |
Congenital muscular dystrophy | 26 |
Distal muscular dystrophy | 9 |
Emery-Dreifuss muscular dystrophy | Nonec |
Limb Girdle muscular dystrophy | 19 |
Myotonic muscular dystrophy | 20 |
Oculopharyngeal muscular dystrophy | None [1] |
Congenital Muscular Dystrophy
Of the 26 Congenital MD studies cited, most are focused on gathering information to better understand the disease. For example, several trials are listed as natural history or genetic studies and some highlight patient- and family-reported medical information. Most of the other studies included diagnostic tests or physical therapy-type studies (e.g., lung stretch therapy).
Distal Muscular Dystrophy
Distal muscular dystrophy was similar to Congenital MD, except with fewer studies; five out of nine studies were listed as “completed” and only two studies reported as recruiting patients.
Limb Girdle Muscular Dystrophy
Limb Girdle muscular dystrophy was similar to Congenital and Distal MDs—meaning that most studies are focused on gathering information to better understand the disease—except that there are more molecular and genetic studies, including gene transfer and stem cell therapy, though the stem cell therapy was for patients with FSHD, not Limb Girdle MD (as accessed on November 7, 2014).
Myotonic Muscular Dystrophy
Most myotonic muscular dystrophy studies focus on the heart and lungs with two notable exceptions: Iplex from Somaokine and Mexiletine.
According to the ADIS database, Iplex, an insulin-like growth factor, was being studied for multiple indications in the Phase II stage of drug development in Europe; however, clinical development had been suspended or discontinued for multiple indications, including MD.
Mexiletine, an orally active local anesthetic agent structurally related to lidocaine, is an approved drug (sponsor Boehringer Ingelheim). This was studied in Italy in a small number of patients with generalized dystonia, but there has been no further development since 2009, according to the ADIS database (as of November 8, 2014).
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