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Table 1.  
Details of New Drugs Approved Between February 1, 2011, and February 29, 2012, and Contact Between the FDA and Pharmaceutical Companies During the Pivotal Study Design Phasea
Details of New Drugs Approved Between February 1, 2011, and February 29, 2012, and Contact Between the FDA and Pharmaceutical Companies During the Pivotal Study Design Phasea
Table 2.  
Drug Approvals in Which the Pharmaceutical Company Did Not Comply With FDA Recommendations About Pivotal Study Design or Primary Outcome
Drug Approvals in Which the Pharmaceutical Company Did Not Comply With FDA Recommendations About Pivotal Study Design or Primary Outcome
1.
 Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients. Fed Regist. 1998;63(231):66631-66672.
PubMed
2.
US Department of Health and Human Services; US Food and Drug Administration. Guidance for industry: special protocol assessment.http://www.fda.gov/downloads/Drugs/Guidances/ucm080571.pdf. Accessed May 8,2014).
3.
US Food and Drug Administration. Drugs@FDA: FDA approved drug products.http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ Accessed June 23, 2014.
4.
Darrow  JJ, Avorn  J, Kesselheim  AS.  New FDA breakthrough-drug category—implications for patients. N Engl J Med. 2014;370(13):1252-1258.
PubMedArticle
5.
US Food and Drug Administration. Independent evaluation of FDA's first cycle review performance—retrospective analysis: final report text. Accessed May 9, 2014. http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm119469.htm).
6.
Sacks  L, Shamsuddin  H, Yasinskaya  Y, Bouri  K, Lanthier  M, Sherman  R. Scientific and regulatory reasons for delay and denial of FDA approval of initial applications for new drugs, 2000-2012. JAMA. 2014;311(4):378-984.
PubMedArticle
Research Letter
November 26, 2014

US Food and Drug Administration and Design of Drug Approval Studies

Author Affiliations
  • 1Center for Medicine and the Media, The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, New Hampshire
  • 2Cornell-Weill Medical School, New York, New York
JAMA. 2014;312(20):2163-2165. doi:10.1001/jama.2014.13329

To enhance protocol quality, federal regulations encourage but do not require meetings between pharmaceutical companies and the US Food and Drug Administration (FDA) during the design phase of pivotal studies assessing drug efficacy and safety for the proposed indication.1 These meetings often generate FDA recommendations for improving research, although companies are not bound to follow them.

Companies can also request special protocol assessments (SPAs) in which the FDA formally reviews the protocol.2 When the FDA endorses an SPA, it agrees not to object to study design, outcomes, or analytic issues when it ultimately reviews the drug for approval, provided the company conducted the trial as planned. We describe interactions between the FDA and pharmaceutical companies to learn how the FDA influences pivotal study design of new drugs.

Methods

We reviewed FDA memos; meeting minutes; filing checklists; and medical, statistical, and summary reviews for all 35 new drugs approved between February 1, 2011, and February 29, 2012. We obtained 172 documents from the FDA website and 28 from Freedom of Information Act requests (16 filing checklists and 12 meeting minutes; available on request). We used a structured form to analyze interactions and abstract comments about studies designated “pivotal” in the medical review during their design phase and quantified company SPA requests and FDA endorsements.

We identified all FDA comments and analyzed recommendations about pivotal study design or primary outcomes. We characterized the effect of recommendations on study quality. Increased meant higher on the evidence pyramid (randomized trial > single group study, patient > surrogate outcome) or stronger methods (eg, validated > unvalidated measures). Two authors (S.W., L.M.S.) characterized the effect of recommendations on study quality (agreement 96%). In addition, we determined compliance in the completed studies.

Stata version 11 (StataCorp) was used for the statistical analyses.

Results

Of 35 new drug approvals (Table 1), companies met with the FDA to discuss pivotal studies for 28. Of the 130 comments made by the FDA, we excluded 77 because they were not recommendations or included redacted or insufficient detail to determine compliance (n = 34), referred to secondary outcomes (n = 4), or were about analytic issues (n = 39).

The FDA made 53 recommendations about design (eg, controls, doses, study length) or primary outcome for 21 approvals (median, 1 [range, 0-7] recommendations per approval). Fifty-one recommendations were judged as increasing study quality (eg, adding controls, blinding, or specific measures and frequency for toxicity assessments, lengthening studies to assess outcome durability) and 2 as having an uncertain effect.

Companies complied with 40 of the 53 recommendations. Table 2 details the 13 cases of noncompliance (involving 10 of the 21 drugs with recommendations). For example, the FDA requested randomized trials of brentuximab and crizotinib, but the companies conducted uncontrolled studies.3 Other cases included primary outcome choice (eg, progression-free instead of overall survival) and drug (active comparator) doses tested.

For 21 of the 35 new drug approvals, companies requested an SPA for a pivotal study protocol and the FDA endorsed 12.

Discussion

Interaction between the FDA and companies during the design phase of pivotal studies led to recommendations for 21 of 35 new drug approvals. Nearly all would have led to stronger study designs and better outcome measures.

Yet companies are not required to meet with the FDA or follow their recommendations. One-quarter of approvals occurred without any meeting, and when such meetings occurred, companies did not comply with one-quarter of recommendations. The FDA endorsed SPAs for only 12 of the 35 approvals, suggesting missed opportunities for optimizing study quality.

One limitation of our study is that we analyzed only approved drugs. Rejected drugs may have lower compliance with recommendations and fewer SPA endorsements.

One approach for enhancing quality of drug approval studies would be to institute mandatory FDA review of pivotal trial protocols with the power to issue binding recommendations, which may be even more important with increasingly flexible approval pathways.4 An independent FDA-commissioned report5 suggested that stronger early FDA involvement could avoid deficiencies that delay approval of effective drugs6 and more clearly identify ineffective or harmful ones.

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Article Information
Section Editor: Jody W. Zylke, MD, Deputy Editor.

Corresponding Author: Lisa M. Schwartz, MD, MS, Center for Medicine and the Media, The Dartmouth Institute for Health Policy and Clinical Practice, 35 Centerra Pkwy, Lebanon, NH 03756 (lisa.schwartz@dartmouth.edu).

Author Contributions: Drs Woloshin and Schwartz had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Woloshin, Schwartz, Faerber.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Woloshin, Schwartz, Faerber.

Administrative, technical, or material support: Frankel, Faerber.

Study supervision: Woloshin, Schwartz.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Woloshin and Schwartz reported being co-founders and shareholders of Informulary Inc, a company that provides data about the benefits, harms, and uncertainties of prescription drugs. No other disclosures were reported.

Additional Contributions: We thank Nancy Morden, MD, MPH (The Dartmouth Institute for Health Policy and Clinical Practice), for helpful comments on an earlier draft of the manuscript. Dr Morden received no compensation for her work.

References
1.
 Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients. Fed Regist. 1998;63(231):66631-66672.
PubMed
2.
US Department of Health and Human Services; US Food and Drug Administration. Guidance for industry: special protocol assessment.http://www.fda.gov/downloads/Drugs/Guidances/ucm080571.pdf. Accessed May 8,2014).
3.
US Food and Drug Administration. Drugs@FDA: FDA approved drug products.http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ Accessed June 23, 2014.
4.
Darrow  JJ, Avorn  J, Kesselheim  AS.  New FDA breakthrough-drug category—implications for patients. N Engl J Med. 2014;370(13):1252-1258.
PubMedArticle
5.
US Food and Drug Administration. Independent evaluation of FDA's first cycle review performance—retrospective analysis: final report text. Accessed May 9, 2014. http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm119469.htm).
6.
Sacks  L, Shamsuddin  H, Yasinskaya  Y, Bouri  K, Lanthier  M, Sherman  R. Scientific and regulatory reasons for delay and denial of FDA approval of initial applications for new drugs, 2000-2012. JAMA. 2014;311(4):378-984.
PubMedArticle
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