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Pink Sheet – Indication Matters: Study Shows Trial Characteristics Of Approved Drugs Vary Widely Across Diseases

Pink Sheet – Indication Matters: Study Shows Trial Characteristics Of Approved Drugs Vary Widely Across Diseases


FDA data requirements supporting novel drug approvals vary widely, depending on therapeutic area, with cancer drugs given greatest leniency, suggesting products may need a clinical trial “quality grade,” according to an analysis published in the Journal of the American Medical Association. Another study shows cancer treatments are most likely to get approved on the first try.

There is wide variation in the quality of clinical trial evidence used by FDA to assess the efficacy of novel therapeutic agents, highlighting the agency’s flexible standards for approval, a new study finds.

“This variation has important implications for patients and physicians as they make decisions about the use of newly approved therapeutic agents and has the potential to inform current FDA regulatory approval standards and post-market surveillance initiatives,” the study authors, led by Nicholas Downing, Yale University School of Medicine, conclude. The authors advocate adopting a system to identify the quality of the information behind an approval.

Not surprisingly, drugs for cancer appear to benefit from a higher degree of flexibility compared to other agents. Overall, trial features differed by therapeutic and indication characteristics, such as therapeutic area, expected length of treatment, orphan status and accelerated approval.

The study examined the pivotal efficacy trials for the 188 novel therapeutic agents approved by FDA between 2005 and 2012. The drugs were approved for 206 indications on the basis of 448 pivotal efficacy trials, according to the findings published in the Journal of the American Medical Association. The Jan. 22/29 issue of the medical journal includes a series of articles looking at FDA approval issues.

Pivotal efficacy trials were classified by their design features: randomization, blinding, comparator, and trial end point. The number of patients, trial duration and trial completion rates were also determined.

Trials for cancer therapies stood out as differing most from the characteristics of the overall pool of pivotal trials (see graph and table below).

Clinical Trial Design For Cancer Vs. Other Therapeutic Areas

Source: Journal of the American Medical Association

For example, while nearly 90% of the 448 trials were randomized, only about 47% of the 55 trials for cancer therapies were randomized. In comparison, all other therapeutic areas examined ranged from being nearly 90% randomized to 100% randomized. Psychiatry, neurology, and autoimmune/musculoskeletal were three therapeutic areas where all of the pivotal trials were randomized. Almost 99% of trials in cardiovascular disease, diabetes mellitus and hyperlipidemia drugs were randomized and 93% of studies on infectious disease drugs were randomized.

Similarly, while about 80% of all of the pivotal efficacy trials were double-blinded only 27.3% of cancer trials had a blinded comparator arm. This compared to the other therapeutic areas were anywhere from about 76% to 100% were double-blinded.

Cancer pivotal trials also had a much lower percentage of active controls and placebo controls, tending to exclude a comparator more than studies in other therapeutic areas. And a much higher percentage of cancer trials used surrogate endpoints compared to other therapeutic areas.

Design of Pivotal Efficacy Trials Providing the Basis for Approval of Novel Therapeutic Agents by FDA Between 2005 and 2012

Agent/Indication Characteristic

(Pivotal Trials)



Active Comparator



No Comparator

Surrogate Endpoint

Clinical Outcome

Clinical Scale

All (n=448)

400 (89.3%)

356 (79.5%)

143 (31.9%)

247 (55.1%)

58 (12.9%)

219 (48.9%)

130 (29%)

99 (22.1%)

Cancer (n=55)

26 (47.3%)

15 (27.3%)

10 (18.2%)

16 (29.1%)

29 (52.7%)

46 (83.6%)

9 (16.4%)


Infectious disease (n=57)

53 (93.0%)

45 (78.9%)

39 (68.4%)

13 (22.8%)

5 (8.8%)

33 (57.9)

24 (42.1%)


Cardiovascular disease, diabetes mellitus, hyperlipidemia (n=73)

72 (98.6%)

68 (93.2%)

26 (35.6%)

45 (61.6%)

2 (2.7%)

62 (84.9%)

11 (15.1%)


Neurology (n=38)

38 (100%)

38 (100%)

6 (15.8%)

30 (78.9%)

2 (5.3%)


25 (65.8%)

13 (34.2%)

Dermatology (n=29)

27 (93.1%)

22 (75.9%)

5 (17.2%)

20 (69%)

4 (13.8%)

5 (17.2%)

15 (51.7%)

9 (31.0%)

Autoimmune/musculoskeletal (n=36)

36 (100%)

34 (94.4%)

11 (30.6%)

25 (69.4%)


6 (16.7%)

2 (5.6%)

28 (77.8%)

Psychiatry (n=43)

43 (100%)

43 (100%)

19 (44.2%)

24 (55.8%)


5 (11.6%)

7 (16.3%)

31 (72.1%)

Other (n=117)

105 (89.7%)

91 (77.8%)

27 (23.1%)

74 (63.2%)

16 (13.7%)

62 (53.0%)

37 (31.6%)

18 (15.4%)

Source: Journal of the American Medical Association

The number of patients in cancer trials tended to be less than those in most other therapeutic categories. The median overall number of patients in all of the pivotal trials was 446 compared to 266 for cancer trials. The median number of patients in the intervention group for all trials was 271 compared to 154 for cancer trials. All other therapeutic areas had numbers closer to, or higher than the median except for dermatology trials which had a median of 233 patients overall and 126 in the intervention group.

Cancer therapies also stood out because the majority was approved on the basis of single trials. The median number of pivotal efficacy trials for cancer treatments was one compared to all other therapeutic areas where the median was at least two (infectious disease, neurology, dermatology, and other) and as high as four (psychiatry). The median number of trials for a cardiovascular disease, diabetes mellitus or hyperlipidemia indication/agent was three. Overall, just more than one-third of indications were approved on the basis of a single pivotal efficacy trial.

The duration of cancer studies however, tended to be longer than the median duration of all the efficacy trials. The median duration of cancer trials was 18.5 weeks compared to 14 weeks for all of the trials.

One factor that didn’t vary too much based on therapeutic area was overall completion rate. For all of the pivotal trials, nearly 87% of patients completed the studies. For individual therapeutic areas only psychiatry had a completion rate below 80%. The completion rate for psychiatry trials was 70.1%. Cancer trials had a completion rate of 82.5%. Dermatology studies had the highest completion rate, at 94.4%.

Orphan Status, Accelerated Approval Also Come With Flexibility

Trials of orphan-designated products and trials for drugs granted accelerated approvals also tended to benefit from the same degree of flexibility as cancer drugs. Earlier studies have also concluded that FDA applies a significant degree of regulatory flexibility when considering orphan drugs (“Orphan Products Mostly Approved With Regulatory Flexibility, NORD “Catalog” Finds” —”The Pink Sheet,” Oct. 17, 2011) and accelerated approvals (“FDA Flexible With Accelerated Approval Evidence, Analysis Finds” — “The Pink Sheet,” Sep. 2, 2013).

The JAMA study found that in these areas, clinical trials were less likely to be randomized and double-blinded and much more likely to have no comparator arm and rely on surrogate outcomes.

For example, about 54% of the 56 trials for orphan-designated products were randomized compared to close to 95% of the 392 trials for products without orphan status.

For accelerated approval, 55% of the 40 trials did not use a comparator, while just under 9% of trials for non-accelerated approval products did not use either a placebo or active comparator.

Surrogate Endpoints Abound, Not Just For Accelerated Approval

The analysis also found that surrogate endpoints were common and not just for those trials approved under the accelerated approval pathway, the formal regulatory pathway that allows for approval based on a surrogate that is “reasonably likely” to predict clinical benefit. Nearly half (219 or 48.9%) of pivotal trials used a surrogate outcome as the primary endpoint. Trials with surrogate endpoints as the primary outcome formed the exclusive basis of approval for 91 of the 201 indications (45.3%).

Among therapeutic agents not undergoing accelerated approval, surrogate endpoints were used in 44.4% of trials. For accelerated approval agents surrogate endpoints were used in nearly all (95%) of trials.

“This reliance on surrogate outcomes leaves patients and physicians to extrapolate clinical benefits from trials, again raising questions about the certainty of the medications’ benefit in practice,” the study authors concluded.

Another notable finding regarding accelerated approval indications compared to non-accelerated approval indications was that there was no difference in the proportion of indications approved through the accelerated approval pathway on the basis of multiple trials when compared with non-accelerated approval indications.

Trials Relatively Short, Even For Chronic Conditions

Long-term efficacy and safety was rarely evaluated in pivotal trials, even for chronic indications. The median trial duration was 14 weeks, with 113 trials, or about 25%, lasting 6 months or longer. The study looked at trial duration for indications based on the expected length of use of the product divided into three categories: acute, intermediate, or chronic. Acute treatments were those for which the expected length of use was less than 1 month. Intermediate treatments have an expected length of use of between 1 month and 2 years and chronic treatments have an expected length of use of greater than 2 years.

Even the majority of chronic treatments were studied in pivotal trials lasting less than one year. Only 13 (12%) of the 108 chronic indications were studied in trials of greater than a year in duration. Forty-eight, or 44.4%, of chronic treatment indications were studied in trials of six months or longer.

In comparison, four (7%) of the 57 intermediate indications were studied in trials of a year or longer and 19, or one-third, of those intermediate indications were studied in trials of six months or longer. For the 36 indications for acute uses, none were studied in trials lasting a year or longer and just one was studied in a trial of six months or longer.

Should Drugs Get A Clinical Trial Quality Grade?

Both the FD&C Act and FDA guidance imply flexibility in drug approval standards, particularly for diseases for which there is no existing effective treatment or poor prognosis, such as cancer or orphan diseases, and this flexibility may be warranted, the authors say. But “flexible approval standards may lead to some therapeutic agents being approved by the FDA on the basis of numerous rigorously designed clinical trials and others on the basis of fewer or less robust studies, leading to different levels of certainty about the risks and benefits of newly approved drugs,” they add.

To address this variance, FDA could consider providing “a summative statement, or even a grade for each product approval to signal the quality of clinical trial evidence used to determine safety and efficacy, allowing therapeutic agents approved on the basis of more robust evidence to be distinguished from those approved on the basis of less robust evidence,” the authors say.

Labeling for products cleared under accelerated approval typically include a statement clarifying that the approval was based on an interim marker, and an effect on the relevant clinical outcome has not yet been established.

The study authors also support a “life-cycle” approach for evaluating drug safety and effectiveness, as discussed in a 2006 Institute of Medicine report on the future of drug safety. The report suggested FDA monitor and evaluate the benefits and risk of drugs throughout their entire market life, not just pre-approval.

The 2006 report led to significant changes at FDA, including steps to emphasize risk management both pre- and post-market and fed into the 2007 FDA Amendments Act, which granted FDA enhanced post-market safety authorities (“IoM Drug Safety Report Recommends Sweeping Changes At CDER” — “The Pink Sheet,” Sep. 25, 2006).

Communicating this updated information to physicians and patients “is critical,” the authors say. They also supported another Institute of Medicine committee suggestion that recommended FDA implement a benefit and risk assessment and management plan that would summarize the FDA’s evaluation of a drug’s benefit-risk profile in a single document that would be updated throughout the market life of the product.

FDA has taken steps to communicate updated safety information about drugs post-market to sponsors since the 2006 IOM report and FDAAA, including implementing the Safety First/Safe Use initiative, which among other items aimed to equip physicians with better tools for safe prescribing habits (“FDA Puts “Safety First” For Post-Market Issues” — “The Pink Sheet” DAILY, Feb. 27, 2008).

Yet despite this discussion of the importance of a life-cycle approach, the evaluation of the clinical trial evidence supporting approval did not take into account any post-marketing commitments, particularly post-marketing trial commitments required for the NMEs.

“It would be helpful to know how many of these approvals, particularly those based on surrogate endpoints, had post-marketing requirements, how many post-market studies were fulfilled, and what was the ultimate clinical assessment of the drugs approved in these various ways,” Steven N. Goodman, Stanford University, and Rita Redberg, University of California, San Francisco, wrote in an accompanying editorial.

Cancer Drugs Also More Likely To Get First-Try OK

Another study conducted by FDA and published in the same issue of JAMA indicates that not only do cancer drugs get significant flexibility regarding clinical trial evidence, but that they are more likely to make it through the agency on the first try.

A review of the 302 new molecular entity applications first submitted to FDA between 2000 and 2012 found that half, or 151, were approved after the first review cycle. However, of the 61 NMEs for cancer treatment, nearly three-quarters were approved during the first review cycle.

In comparison, all other medical specialties saw less than 60% approved on the first cycle except for gastroenterology, which saw 69% of products approved on the first try.

Pulmonary and allergy drugs had the lowest percentage of drugs approved on the first cycle (31%, 4/13). Cardiology drugs fared just slightly better with 32% (7/22) being approved on the first cycle. Neurology/psychiatry and dermatology products also showed particularly low first-cycle approval rates, coming in at just 33% being approved on the first try (see graph). Neurology drugs had one of the lowest first-cycle approval rates despite being the third-highest number of submissions among the 14 specialties analyzed.

First Cycle Approval Rates By Medical Specialty

Source: Journal of the American Medical Association

FDA’s review offers a rare look into the reasons for drug denials and delays, as the agency generally interprets the law as prohibiting it from sharing data for unapproved drugs or commenting on reasons for a “complete response.” The study found that many of the drug applications rejected by FDA are not due to lack of efficacy or safety but are because the information submitted with the application was not satisfactory to make a determination of efficacy and safety (“Many Drug Approval Delays, Denials Could Be Prevented, FDA Study Shows” — “The Pink Sheet” DAILY, Jan. 21, 2014).

Efficacy deficiencies such as uncertainty/disagreement about appropriate dose, use of unsatisfactory endpoints, and clinical trials that studied populations that did not reflect the populations likely to use the drug were cited as three primary reasons for failure that could have potentially been avoided by, for example, earlier and more frequent dialogue with FDA and more dose exploration.…;